Amino acids with affinity for the alpha2delta-protein

ABSTRACT

This invention relates to certain β-amino acids that bind to the alpha-2-delta (α2δ) subunit of a calcium channel. These compounds and their pharmaceutically acceptable salts are useful in the treatment of a variety of psychiatric pain and other disorders.

This application claims the benefit of U.S. Provisional Application No.60/368,413 filed Mar. 28, 2002.

BACKGROUND OF THE INVENTION

This invention relates to certain β-amino acids that bind to thealpha-2-delta (α2δ) subunit of a calcium channel. These compounds andtheir pharmaceutically acceptable salts are useful in the treatment of avariety of psychiatric, pain and other disorders.

SUMMARY OF THE INVENTION

This invention relates to compounds of the formula I

wherein R₁ is hydrogen or (C₁-C₆)alkyl optionally substituted with fromone to five fluorine atoms;

R₂ is hydrogen or (C₁-C₆)alkyl optionally substituted with from one tofive fluorine atoms; or

R₁ and R₂, together with the carbon to which they are attached, form athree to six membered cycloalkyl ring;

R₃ is (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl-(C₁-C₃)alkyl,phenyl, phenyl-(C₁-C₃)alkyl, pyridyl, pyridyl-(C₁-C₃)alkyl,phenyl-N(H)—, or pyridyl-N(H)—, wherein each of the foregoing alkylmoieties can be optionally substituted with from one to five fluorineatoms, preferably with from zero to three fluorine atoms, and whereinsaid phenyl and said pyridyl and the phenyl and pyridyl moieties of saidphenyl-(C₁-C₃)alkyl and said pyridyl-(C₁-C₃)alkyl, respectively, can beoptionally substituted with from one to three substituents, preferablywith from zero to two substituents, independently selected from chloro,fluoro, amino, nitro, cyano, (C₁-C₃)alkylamino, (C₁-C₃)alkyl optionallysubstituted with from one to three fluorine atoms and (C₁-C₃)alkoxyoptionally substituted with from one to three fluorine atoms;

R₄ is hydrogen or (C₁-C₆)alkyl optionally substituted with from one tofive fluorine atoms;

R₅ is hydrogen or (C₁-C₆)alkyl optionally substituted with from one tofive fluorine atoms; and

R₆ is hydrogen or (C₁-C₆)alkyl;

and the pharmaceutically acceptable salts of such compounds.

Specific embodiments of this invention include the following compoundsof the formula I and their pharmaceutically acceptable salts:

3-Amino-5,8-dimethyl-nonanoic acid;

3-Amino-5,5,7-trimethyl-octanoic acid;

3-Amino-5,5,8-trimethyl-nonanoic acid;

3-Amino-5,5,6-trimethyl-heptanoic acid;

(3S,5S)-3-Amino-5,8-dimethyl-nonanoic acid;

(3S,5R)-3-Amino-5,8-dimethyl-nonanoic acid;

(3S)-3-Amino-5,5,6-trimethyl-heptanoic acid;

(3S)-3-Amino-5,5,7-trimethyl-octanoic acid;

(3S)-3-Amino-5,5,8-trimethyl-nonanoic acid; and

(3S)-3-Amino-5,5,9-trimethyl-decanoic acid.

Other examples of specific embodiments of this invention are thefollowing compounds of the formula I and their pharmaceuticallyacceptable salts:

3-Amino-6-cyclobutyl-5-methyl-hexanoic acid;

3-Amino-7-cyclopropyl-5-methyl-heptanoic acid;

3-Amino-7-cyclobutyl-5-methyl-heptanoic acid;

3-Amino-7-cyclopentyl-5-methyl-heptanoic acid;

3-Amino-7-cyclohexyl-5-methyl-heptanoic acid;

3-Amino-8-cyclopropyl-5-methyl-octanoic acid;

3-Amino-8-cyclobutyl-5-methyl-octanoic acid;

3-Amino-8-cyclopentyl-5-methyl-octanoic acid;

3-Amino-8-cyclohexyl-5-methyl-octanoic acid;

3-Amino-6-cyclopropyl-5,5-dimethyl-hexanoic acid;

3-Amino-6-cyclobutyl-5,5-dimethyl-hexanoic acid;

3-Amino-6-cyclopentyl-5,5-dimethyl-hexanoic acid;

3-Amino-6-cyclohexyl-5,5-dimethyl-hexanoic acid;

3-Amino-7-cyclopropyl-5,5-dimethyl-heptanoic acid;

3-Amino-7-cyclobutyl-5,5-dimethyl-heptanoic acid;

3-Amino-7-cyclopentyl-5,5-dimethyl-heptanoic acid;

3-Amino-7-cyclohexyl-5,5-dimethyl-heptanoic acid;

(3S,5R)-3-Amino-6-cyclobutyl-5-methyl-hexanoic acid;

(3S,5R)-3-Amino-7-cyclopropyl-5-methyl-heptanoic acid;

(3S,5R)-3-Amino-7-cyclobutyl-5-methyl-heptanoic acid;

(3S,5R)-3-Amino-7-cyclopentyl-5-methyl-heptanoic acid;

(3S,5R)-3-Amino-7-cyclohexyl-5-methyl-heptanoic acid;

(3S,5R)-3-Amino-8-cyclopropyl-5-methyl-octanoic acid;

(3S,5R)-3-Amino-8-cyclobutyl-5-methyl-octanoic acid;

(3S,5R)-3-Amino-8-cyclopentyl-5-methyl-octanoic acid;

(3S,5R)-3-Amino-8-cyclohexyl-5-methyl-octanoic acid;

(3S,5S)-3-Amino-6-cyclobutyl-5-methyl-hexanoic acid;

(3S,5S)-3-Amino-7-cyclopropyl-5-methyl-heptanoic acid;

(3S,5S)-3-Amino-7-cyclobutyl-5-methyl-heptanoic acid;

(3S,5S)-3-Amino-7-cyclopentyl-5-methyl-heptanoic acid;

(3S,5S)-3-Amino-7-cyclohexyl-5-methyl-heptanoic acid;

(3S,5S)-3-Amino-8-cyclopropyl-5-methyl-octanoic acid;

(3S,5S)-3-Amino-8-cyclobutyl-5-methyl-octanoic acid;

(3S,5S)-3-Amino-8-cyclopentyl-5-methyl-octanoic acid;

(3S,5S)-3-Amino-8-cyclohexyl-5-methyl-octanoic acid;

(3S)-3-Amino-6-cyclopropyl-5,5-dimethyl-hexanoic acid;

(3S)-3-Amino-6-cyclobutyl-5,5-dimethyl-hexanoic acid;

(3S)-3-Amino-6-cyclopentyl-5,5-dimethyl-hexanoic acid;

(3S)-3-Amino-6-cyclohexyl-5,5-dimethyl-hexanoic acid;

(3S)-3-Amino-7-cyclopropyl-5,5-dimethyl-heptanoic acid;

(3S)-3-Amino-7-cyclobutyl-5,5-dimethyl-heptanoic acid;

(3S)-3-Amino-7-cyclopentyl-5,5-dimethyl-heptanoic acid; and

(3S)-3-Amino-7-cyclohexyl-5,5-dimethyl-heptanoic acid;

Other specific embodiments of this invention include the followingcompounds of the formula I and their pharmaceutically acceptable salts:

3-Amino-5-methyl-heptanoic acid;

3-Amino-5-methyl-octanoic acid;

3-Amino-5-methyl-nonanoic acid;

3-Amino-5,5-dimethyl-nonanoic acid;

3-Amino-5,5-dimethyl-decanoic acid;

(3S)-3-Amino-5,5-dimethyl-nonanoic acid; and

(3S)-3-Amino-5,5-dimethyl-decanoic acid.

This invention also relates to compounds of the formula IA:

wherein R₁ is hydrogen or (C₁-C₃)alkyl optionally substituted with fromone to five fluorine atoms;

R₂ is hydrogen or (C₁-C₃)alkyl optionally substituted with from one tofive fluorine atoms; or

R₁ and R₂, together with the carbon to which they are attached, form athree to six membered cycloalkyl ring;

R₃ is (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl-(C₁-C₃)alkyl,phenyl, phenyl-(C₁-C₃)alkyl, pyridyl, pyridyl-(C₁-C₃)alkyl,phenyl-N(H)—, or pyridyl-N(H)—, wherein each of the foregoing alkylmoieties can be optionally substituted with from one to five fluorineatoms, preferably with from zero to three fluorine atoms, and whereinsaid phenyl and said pyridyl and the phenyl and pyridyl moieties of saidphenyl-(C₁-C₃)alkyl and said pyridyl-(C₁-C₃)alkyl, respectively, can beoptionally substituted with from one to three substituents, preferablywith from zero to two substituents, independently selected from chloro,fluoro, amino, nitro, cyano, (C₁-C₃)alkylamino, (C₁-C₃)alkyl optionallysubstituted with from one to three fluorine atoms and (C₁-C₃)alkoxyoptionally substituted with from one to three fluorine atoms;

with the proviso that when R₁ is hydrogen, R₂ is not hydrogen; and thepharmaceutically acceptable salts of such compounds.

This invention also relates to compounds of the formula IA-1

wherein R₃ is defined as for formula I above, and the pharmaceuticallyacceptable salts of such compounds.

Other specific embodiments of this invention include the followingcompounds of the formula IA and their pharmaceutically acceptable salts:

3-Amino-5-methyl-8-phenylamino-octanoic acid;

3-Amino-5-methyl-7-phenylamino-heptanoic acid;

3-Amino-5-methyl-6-phenylamino-hexanoic acid;

(3S, 5R)-3-Amino-5-methyl-8-phenylamino-octanoic acid;

(3S, 5R)-3-Amino-5-methyl-7-phenylamino-heptanoic acid;

(3S, 5R)-3-Amino-5-methyl-6-phenylamino-hexanoic acid;

(3S, 5S)-3-Amino-5-methyl-8-phenylamino-octanoic acid;

(3S, 5S)-3-Amino-5-methyl-7-phenylamino-heptanoic acid;

(3S, 5S)-3-Amino-5-methyl-6-phenylamino-hexanoic acid;

3-Amino-5-methyl-8-phenyl-octanoic acid;

3-Amino-8-(2-fluoro-phenyl)-5-methyl-octanoic acid;

3-Amino-8-(3-fluoro-phenyl)-5-methyl-octanoic acid;

3-Amino-8-(4-fluoro-phenyl)-5-methyl-octanoic acid;

3-Amino-8-(2-trifluoro-phenyl)-5-methyl-octanoic acid;

3-Amino-8-(3-trifluoro-phenyl)-5-methyl-octanoic acid;

3-Amino-8-(4-trifluoro-phenyl)-5-methyl-octanoic acid;

3-Amino-5-methyl-8-o-tolyl-octanoic acid;

3-Amino-5-methyl-8-m-tolyl-octanoic acid;

3-Amino-5-methyl-8-p-tolyl-octanoic acid;

3-Amino-5-methyl-8-p-tolyl-octanoic acid;

3-Amino-8-(2,3-difluoro-phenyl)-5-methyl-octanoic acid;

3-Amino-8-(2,4-difluoro-phenyl)-5-methyl-octanoic acid;

3-Amino-8-(2,5-difluoro-phenyl)-5-methyl-octanoic acid;

3-Amino-8-(2,6-difluoro-phenyl)-5-methyl-octanoic acid;

(3S,5R)-3-Amino-5-methyl-8-phenyl-octanoic acid;

(3S,5S)-3-Amino-5-methyl-8-phenyl-octanoic acid;

(3S,5R)-3-Amino-8-(2-fluoro-phenyl)-5-methyl-octanoic acid;

(3S,5S)-3-Amino-8-(2-fluoro-phenyl)-5-methyl-octanoic acid;

(3S, 5R)-3-Amino-8-(3-fluoro-phenyl)-5-methyl-octanoic acid;

(3S, 5S)-3-Amino-8-(3-fluoro-phenyl)-5-methyl-octanoic acid;

(3S, 5R)-3-Amino-8-(4-fluoro-phenyl)-5methyl-octanoic acid;

(3S, 5S)-3-Amino-8-(4-fluoro-phenyl)-5-methyl-octanoic acid;

(3S, 5R)-3-Amino-8-(2-trifluoro-phenyl)-5-methyl-octanoic acid;

(3S, 5S)-3-Amino-8-(2-trifluoro-phenyl)-5-methyl-octanoic acid;

(3S, 5R)-3-Amino-8-(3-trifluoro-phenyl)-5-methyl-octanoic acid;

(3S, 5S)-3-Amino-8-(3-trifluoro-phenyl)-5-methyl-octanoic acid;

(3S, 5R)-3-Amino-8-(4-trifluoro-phenyl)-5-methyl-octanoic acid;

(3S, 5S)-3-Amino-8-(4-trifluoro-phenyl)-5-methyl-octanoic acid;

(3S, 5R)-3-Amino-5-methyl-8-o-tolyl-octanoic acid;

(3S, 5S)-3-Amino-5-methyl-8-o-tolyl-octanoic acid;

(3S, 5R)-3-Amino-5-methyl-8-m-tolyl-octanoic acid;

(3S, 5S)-3-Amino-5-methyl-8-m-tolyl-octanoic acid;

(3S, 5R)-3-Amino-5-methyl-8-p-tolyl-octanoic acid

(3S, 5S)-3-Amino-5-methyl-8-p-tolyl-octanoic acid;

(3S, 5R)-3-Amino-8-(2,3-difluoro-phenyl)5-methyl-octanoic acid;

(3S, 5S)-3-Amino-8-(2,3-difluoro-phenyl)5-methyl-octanoic acid;

(3S, 5R)-3-Amino-8-(2,4-difluoro-phenyl)5-methyl-octanoic acid;

(3S, 5S)-3-Amino-8-(2,4-difluoro-phenyl)5-methyl-octanoic acid;

(3S, 5R)-3-Amino-8-(2,5-difluoro-phenyl)5-methyl-octanoic acid;

(3S, 5S)-3-Amino-8-(2,5-difluoro-phenyl)5-methyl-octanoic acid;

(3S, 5R)-3-Amino-8-(2,6-difluoro-phenyl)-5-methyl-octanoic acid; and

(3S, 5S)-3-Amino-8-(2,6-difluoro-phenyl)-5-methyl-octanoic acid.

Preferred compounds of this invention include those of the formula IA-2,

wherein R₁, R₂, and R₃ are defined as for formula I above.

Examples of more preferred compounds of this invention are compounds ofthe formula IA-2 wherein R₁ is hydrogen, R₂ is methyl and R₃ is definedas for formula I above.

Examples of specific embodiments of this invention are the followingcompounds of the formula IA-2 and their pharmaceutically acceptablesalts:

(3S,5R)-3-Amino-5-methyl-heptanoic acid;

(3S,5R)-3-Amino-5-methyl-octanoic acid; and

(3S,5R)-3-Amino-5-methyl-nonanoic acid.

This invention also relates to compounds of the formula IB

and their pharmaceutically acceptable salts wherein R₃ is defined asabove and wherein said compounds are selected from the followingcompounds and their pharmaceutically acceptable salts:

3-Amino-4,5-dimethyl-hexanoic acid;

3-Amino-4,6-dimethyl-heptanoic acid;

3-Amino-4,7-dimethyl-octanoic acid;

3-Amino-4,8-methyl-nonanoic acid;

3-Amino-4,9-dimethyl-decanoic acid;

3-Amino-4-cyclopropyl-pentanoic acid;

3-Amino-4-cyclobutyl-pentanoic acid;

3-Amino-4-cyclopentyl-pentanoic acid;

3-Amino-4-cyclohexyl-pentanoic acid;

3-Amino-5-cyclopropyl-4-methyl-pentanoic acid;

3-Amino-5-cyclobutyl-4-methyl-pentanoic acid;

3-Amino-5-cyclopentyl-4-methyl-pentanoic acid;

3-Amino-5-cyclohexyl-4-methyl-pentanoic acid;

3-Amino-6-cyclopropyl-4-methyl-hexanoic acid;

3-Amino-6-cyclobutyl-4-methyl-hexanoic acid;

3-Amino-6-cyclopentyl-4-methyl-hexanoic acid;

3-Amino-6-cyclohexyl-4-methyl-hexanoic acid;

3-Amino-7-cyclopropyl-4-methyl-heptanoic acid;

3-Amino-7-cyclobutyl-4-methyl-heptanoic acid;

3-Amino-7-cyclopentyl4-methyl-heptanoic acid;

3-Amino-7-cyclohexyl-4-methyl-heptanoic acid;

3-Amino-8-cyclopropyl-4-methyl-octanoic acid;

3-Amino-8-cyclobutyl-4-methyl-octanoic acid;

3-Amino-8-cyclopentyl-4-methyl-octanoic acid;

3-Amino-8-cyclohexyl-4-methyl-octanoic acid;

3-Amino-9-cyclopropyl-4-methyl-nonanoic acid;

3-Amino-9-cyclobutyl-4-methyl-nonanoic acid;

3-Amino-9-cyclopentyl4-methyl-nonanoic acid;

3-Amino-9-cyclohexyl4-methyl-nonanoic acid;

3-Amino4-methyl-octanoic acid;

3-Amino-4-methyl-nonanoic acid;

3-Amino-4-methyl-decanoic acid;

(3R, 4R)-3-Amino-4,5-dimethyl-hexanoic acid;

(3R, 4R)-3-Amino-4,6-dimethyl-heptanoic acid;

(3R, 4R)-3-Amino4,7-dimethyl-octanoic acid;

(3R, 4R)-3-Amino-4,8-dimethyl-nonanoic acid;

(3R, 4R)-3-Amino-4,9-dimethyl-decanoic acid;

(3R, 4R)-3-Amino-4-cyclopropyl-pentanoic acid;

(3R, 4R)-3-Amino-4-cyclobutyl-pentanoic acid;

(3R, 4R)-3-Amino-4-cyclopentyl-pentanoic acid;

(3R, 4R)-3-Amino-4-cyclohexyl-pentanoic acid;

(3R, 4R)-3-Amino-5-cyclopropyl4-methyl-pentanoic acid;

(3R, 4R)-3-Amino-5-cyclobutyl-4-methyl-pentanoic acid;

(3R, 4R)-3-Amino-5-cyclopentyl-4-methyl-pentanoic acid;

(3R, 4R)-3-Amino-5-cyclohexyl-4-methyl-pentanoic acid;

(3R, 4R)-3-Amino-6-cyclopropyl-4-methyl-hexanoic acid;

(3R, 4R)-3-Amino-6-cyclobutyl-4-methyl-hexanoic acid;

(3R, 4R)-3-Amino-6-cyclopentyl4-methyl-hexanoic acid;

(3R, 4R)-3-Amino-6-cyclohexyl-4-methyl-hexanoic acid;

(3R, 4R)-3-Amino-7-cyclopropyl-4-methyl-heptanoic acid;

(3R, 4R)-3-Amino-7-cyclobutyl-4-methyl-heptanoic acid;

(3R, 4R)-3-Amino-7-cyclopentyl-4-methyl-heptanoic acid;

(3R, 4R)-3-Amino-7-cyclohexyl-4-methyl-heptanoic acid;

(3R, 4R)-3-Amino-8-cyclopropyl-4-methyl-octanoic acid;

(3R, 4R)-3-Amino-8-cyclobutyl-4-methyl-octanoic acid;

(3R, 4R)-3-Amino-8-cyclopentyl4-methyl-octanoic acid;

(3R, 4R)-3-Amino-8-cyclohexyl-4-methyl-octanoic acid;

(3R, 4R)-3-Amino-9-cyclopropyl-4-methyl-nonanoic acid;

(3R, 4R)-3-Amino-9-cyclobutyl-4methyl-nonanoic acid;

(3R, 4R)-3-Amino-9-cyclopentyl4-methyl-nonanoic acid;

(3R, 4R)-3-Amino-9-cyclohexyl4-methyl-nonanoic acid;

(3R, 4R)-3-Amino-4-methyloctanoic acid;

(3R, 4R)-3-Amino-4-methyl-nonanoic acid;

(3R, 4R)-3-Amino-4-methyl-decanoic acid;

(3R, 4S)-3-Amino4,5-dimethyl-hexanoic acid;

(3R, 4S)-3-Amino-4,6-dimethyl-heptanoic acid;

(3R, 4S)-3-Amino-4,7-dimethyl-octanoic acid;

(3R, 4S)-3-Amino-4,8-dimethyl-nonanoic acid;

(3R, 4S)-3-Amino-4,9-dimethyl-decanoic acid;

(3R, 4S)-3-Amino-4-cyclopropyl-pentanoic acid;

(3R, 4S)-3-Amino-4-cyclobutyl-pentanoic acid;

(3R, 4S)-3-Amino-4-cyclopentyl-pentanoic acid;

(3R, 4S)-3-Amino-4-cyclohexyl-pentanoic acid;

(3R, 4S)-3-Amino-5-cyclopropyl-4-methyl-pentanoic acid;

(3R, 4S)-3-Amino-5-cyclobutyl-4-methyl-pentanoic acid;

(3R, 4S)-3-Amino-5-cyclopentyl-4-methyl-pentanoic acid;

(3R, 4S)-3-Amino-5-cyclohexyl-4-methyl-pentanoic acid;

(3R, 4S)-3-Amino-6-cyclopropyl-4-methyl-hexanoic acid;

(3R, 4S)-3-Amino-6-cyclobutyl-4-methyl-hexanoic acid;

(3R, 4S)-3-Amino-6-cyclopentyl4-methyl-hexanoic acid;

(3R, 4S)-3-Amino-6-cyclohexyl-4-methyl-hexanoic acid;

(3R, 4S)-3-Amino-7-cyclopropyl-4-methyl-heptanoic acid;

(3R, 4S)-3-Amino-7-cyclobutyl-4-methyl-heptanoic acid;

(3R, 4S)-3-Amino-7-cyclopentyl-4-methyl-heptanoic acid;

(3R, 4S)-3-Amino-7-cyclohexyl-4-methyl-heptanoic acid;

(3R, 4S)-3-Amino-8-cyclopropyl-4-methyl-octanoic acid;

(3R, 4S)-3-Amino-8-cyclobutyl-4-methyl-octanoic acid;

(3R, 4S)-3-Amino-8-cyclopentyl-4-methyl-octanoic acid;

(3R, 4S)-3-Amino-8-cyclohexyl4-methyl-octanoic acid;

(3R, 4S)-3-Amino-9-cyclopropyl-4-methyl-nonanoic acid;

(3R, 4S)-3-Amino-9-cyclobutyl4-methyl-nonanoic acid;

(3R, 4S)-3-Amino-9-cyclopentyl4-methyl-nonanoic acid;

(3R, 4S)-3-Amino-9-cyclohexyl-4-methyl-nonanoic acid;

(3R, 4S)-3-Amino-4-methyl-octanoic acid;

(3R, 4S)-3-Amino-4-methyl-nonanoic acid; and

(3R, 4S)-3-Amino-4-methyl-decanoic acid.

This invention also relates to the compounds of the formula IC

and their pharmaceutically acceptable salts wherein R₃ is defined asabove and wherein said compounds are selected from the followingcompounds and their pharmaceutically acceptable salts:

3-Amino-6-methyl-decanoic acid;

3-Amino-6-cyclopropyl-heptanoic acid;

3-Amino-6-cyclobutyl-heptanoic acid;

3-Amino-6-cyclopentyl-heptanoic acid;

3-Amino-6-cyclohexyl-heptanoic acid;

3-Amino-7-cyclopropyl-6-methyl-heptanoic acid;

3-Amino-7-cyclobutyl-6-methyl-heptanoic acid;

3-Amino-7-cyclopentyl-6-methyl-heptanoic acid;

3-Amino-7-cyclohexyl-6-methyl-heptanoic acid;

3-Amino-8-cyclopropyl-6-methyl-octanoic acid;

3-Amino-8-cyclobutyl-6-methyl-octanoic acid;

3-Amino-8-cyclopentyl-6-methyl-octanoic acid;

3-Amino-8-cyclohexyl-6-methyl-octanoic acid;

3-Amino-9-cyclopropyl-6-methyl-nonanoic acid;

3-Amino-9-cyclobutyl-6-methyl-nonanoic acid;

3-Amino-9-cyclopentyl-6-methyl-nonanoic acid;

3-Amino-9-cyclohexyl-6-methyl-nonanoic acid;

3-Amino-10-cyclopropyl-6-methyl-decanoic acid;

3-Amino-10-cyclobutyl-6-methyl-decanoic acid;

3-Amino-10-cyclopentyl-6-methyl-decanoic acid;

3-Amino-10-cyclohexyl-6-methyl-decanoic acid;

3-Amino-6-isopropyl-heptanoic acid;

3-Amino-6,8-dimethyl-nonanoic acid;

3-Amino-6,9-dimethyl-decanoic acid;

(3S, 6R)-3-Amino-6-methyl-decanoic acid;

(3S, 6R)-3-Amino-6-cyclopropyl-heptanoic acid;

(3S, 6R)-3-Amino-6-cyclobutyl-heptanoic acid;

(3S, 6R)-3-Amino-6-cyclopentyl-heptanoic acid;

(3S, 6R)-3-Amino-6cyclohexyl-heptanoic acid;

(3S, 6R)-3-Amino-7-cyclopropyl-6-methyl-heptanoic acid;

(3S, 6R)-3-Amino-7-cyclobutyl-6-methyl-heptanoic acid;

(3S, 6R)-3-Amino-7-cyclopentyl-6-methyl-heptanoic acid;

(3S, 6R)-3-Amino-7-cyclohexyl-6-methyl-heptanoic acid;

(3S, 6R)-3-Amino-8-cyclopropyl-6-methyl-octanoic acid;

(3S, 6R)-3-Amino-8-cyclobutyl-6-methyl-octanoic acid;

(3S, 6R)-3-Amino-8-cyclopentyl-6-methyl-octanoic acid;

(3S, 6R)-3-Amino-8-cyclohexyl-6-methyl-octanoic acid;

(3S, 6R)-3-Amino-9-cyclopropyl-6-methyl-nonanoic acid;

(3S, 6R)-3-Amino-9-cyclobutyl-6-methyl-nonanoic acid;

(3S, 6R)-3-Amino-9-cyclopentyl-6-methyl-nonanoic acid;

(3S, 6R)-3-Amino-9-cyclohexyl-6-methyl-nonanoic acid;

(3S, 6R)-3-Amino- 10-cyclopropyl-6-methyl-decanoic acid;

(3S, 6R)-3-Amino-10-cyclobutyl-6-methyl-decanoic acid;

(3S, 6R)-3-Amino-10-cyclopentyl-6-methyl-decanoic acid;

(3S, 6R)-3-Amino-10-cyclohexyl-6-methyl-decanoic acid;

(3S, 6R)-3-Amino-6-isopropyl-heptanoic acid;

(3S, 6R)-3-Amino-6,8-dimethyl-nonanoic acid;

(3S, 6R)-3-Amino-6,9-dimethyl-decanoic acid;

(3S, 6S)-3-Amino-6-methyl-octanoic acid;

(3S, 6S)-3-Amino-6-methyl-nonanoic acid;

(3S, 6S)-3-Amino-6-methyl-decanoic acid;

(3S, 6S)-3-Amino-6-cyclopropyl-heptanoic acid;

(3S, 6S)-3-Amino-6-cyclobutyl-heptanoic acid;

(3S, 6S)-3-Amino-6-cyclopentyl-heptanoic acid;

(3S, 6S)-3-Amino-6-cyclohexyl-heptanoic acid;

(3S, 6S)-3-Amino-7-cyclopropyl-6-methyl-heptanoic acid;

(3S, 6S)-3-Amino-7-cyclobutyl-6-methyl-heptanoic acid;

(3S, 6S)-3-Amino-7-cyclopentyl-6-methyl-heptanoic acid;

(3S, 6S)-3-Amino-7-cyclohexyl-6-methyl-heptanoic acid;

(3S, 6S)-3-Amino-8-cyclopropyl-6-methyl-octanoic acid;

(3S, 6S)-3-Amino-8-cyclobutyl-6-methyl-octanoic acid;

(3S, 6S)-3-Amino-8-cyclopentyl-6-methyl-octanoic acid;

(3S, 6S)-3-Amino-8-cyclohexyl-6-methyl-nonanoic acid;

(3S, 6S)-3-Amino-9-cyclopropyl-6-methyl-nonanoic acid;

(3S, 6S)-3-Amino-9-cyclobutyl-6-methyl-nonanoic acid;

(3S, 6S)-3-Amino-9-cyclopentyl-6-methyl-nonanoic acid;

(3S, 6S)-3-Amino-9-cyclohexyl-6-methyl-nonanoic acid;

(3S, 6S)-3-Amino-10-cyclopropyl-6-methyl-decanoic acid;

(3S, 6S)-3-Amino-10-cyclobutyl-6-methyl-decanoic acid;

(3S, 6S)-3-Amino-10-cyclopentyl-6-methyl-decanoic acid;

(3S, 6S)-3-Amino-1 0-cyclohexyl-6-methyl-decanoic acid;

(3S, 6S)-3-Amino-6-isopropyl-heptanoic acid;

(3S, 6S)-3-Amino-6,8-dimethyl-nonanoic acid; and

(3S, 6S)-3-Amino-6,9-dimethyl-decanoic acid.

This invention also relates to compounds of the formula II:

wherein R₁, R₂, and R₃ are defined as for formula I above, and thepharmaceutically acceptable salts of such compounds.

Examples of specific embodiments of this invention are the followingcompound of formula IV and its pharmaceutically acceptable salts:2-aminomethyl4-propyl-heptanoic acid.

This invention also relates to compounds of the formula IIA

wherein R₃ is defined as for formula I above, and the pharmaceuticallyacceptable salts of such compounds.

Other specific embodiments of this invention include the followingcompounds of the formula II and their pharmaceutically acceptable salts:

2-Aminomethyl4-methyl-7-phenyl-heptanoic acid;

2-Aminomethyl4-methyl-6phenyl-hexanoic acid;

2-Aminomethyl-7-(4-fluoro-phenyl)-4-methyl-heptanoic acid;

2-Aminomethyl-7-(3-fluoro-phenyl)-4-methyl-heptanoic acid;

2-Aminomethyl-7-(2-fluoro-phenyl)-4-methyl-heptanoic acid;

2-Aminomethyl-7-(2,4-difluoro-phenyl)-4-methyl-heptanoic acid;

2-Aminomethyl-7-(3,4-difluoro-phenyl)-4-methyl-heptanoic acid;

2-Aminomethyl-4-methyl-7-(2-trifluoromethyl-phenyl)-heptanoic acid;

2-Aminomethyl-4-methyl-7-(3-trifluoromethyl-phenyl)-heptanoic acid;

2-Aminomethyl4-methyl-7-(4-trifluoromethyl-phenyl)-heptanoic acid;

2-Aminomethyl-4-methyl-6-phenylamino-hexanoic acid;

2-Aminomethyl-4-methyl-7-phenylamino-heptanoic acid;

2-Aminomethyl-4-methyl-8-phenylamino-octanoic acid;

(2R, 4R)-2-Aminomethyl-4-methyl-7-phenyl-heptanoic acid;

(2R, 4R)-2-Aminomethyl-4-methyl-6-phenyl-hexanoic acid;

(2R,4R)-2-Aminomethyl-7-(4-fluoro-phenyl)-4-methyl-heptanoic acid;

(2R,4R)-2-Aminomethyl-7-(3-fluoro-phenyl)-4-methyl-heptanoic acid;

(2R,4R)-2-Aminomethyl-7-(2-fluoro-phenyl)-4-methyl-heptanoic acid;

(2R,4R)-2-Aminomethyl-7-(2,4-difluoro-phenyl)-4-methyl-heptanoic acid;

(2R ,4R)-2-Aminomethyl-7-(3,4-difluoro-phenyl)-4-methyl-heptanoic acid;

(2R ,4R)-2-Aminomethyl-4-methyl-7-(2-trifluoromethyl-phenyl)-heptanoicacid;

(2R ,4R)-2-Aminomethyl-4-methyl-7-(3-trifluoromethyl-phenyl)-heptanoicacid;

(2R,4R)-2-Aminomethyl-4-methyl-7-(4-trifluoromethyl-phenyl)-heptanoicacid;

(2R,4R)-2-Aminomethyl-4-methyl-6-phenylamino-hexanoic acid;

(2R,4R)-2-Aminomethyl-4-methyl-7-phenylamino-heptanoic acid;

(2R,4R)-2-Aminomethyl-4-methyl-8-phenylamino-octanoic acid;

(2R,4S)-2-Aminomethyl4-methyl-7-phenyl-heptanoic acid;

(2R,4S)-2-Aminomethyl-4-methyl-6-phenyl-hexanoic acid;

(2R,4S)-2-Aminomethyl-7-(4-fluoro-phenyl)-4-methyl-heptanoic acid;

(2R,4S)-2-Aminomethyl-7-(3-fluoro-phenyl)-4-methyl-heptanoic acid;

(2R,4S)-2-Aminomethyl-7-(2-fluoro-phenyl)-4-methyl-heptanoic acid;

(2R,4S)-2-Aminomethyl-7-(2 ,4-difluoro-phenyl)-4-methyl-heptanoic acid;

(2R,4S)-2-Aminomethyl-7-(3,4-difluoro-phenyl)-4-methyl-heptanoic acid;

(2R,4S)-2-Aminomethyl-4-methyl-7-(2-trifluoromethyl-phenyl)-heptanoicacid;

(2R,4S)-2-Aminomethyl-4-methyl-7-(3-trifluoromethyl-phenyl)-heptanoicacid;

(2R,4S)-2-Aminomethyl-4-methyl-7-(4-trifIuoromethyl-phenyl)-heptanoicacid;

(2R,4S)-2-Aminomethyl-4-methyl-6-phenylamino-hexanoic acid;

(2R,4S)-2-Aminomethyl4-methyl-7-phenylamino-heptanoic acid;

(2R,4S)-2-Aminomethyl-4-methyl-8-phenylamino-octanoic acid;

(2R, 4S)-2-Aminomethyl-6-cyclohexyl-4-ethyl-hexanoic acid;

2-Aminomethyl-3-(1-methyl-cyclopropyl)-propionic acid

2-Aminomethyl-3-(1-ethyl-cyclopropyl)-propionic acid

2-Aminomethyl-3-(1-propyl-cyclopropyl)-propionic acid

2-Aminomethyl-3-(1-isopropyl-cyclopropyl)-propionic acid

2-Aminomethyl-3-(1-butyl-cyclopropyl)-propionic acid

2-Aminomethyl-3-(1-isobutyl-cyclopropyl)-propionic acid

2-Aminomethyl-3-[1(4-methyl-pentyl)-cyclopropyl]-propionic acid

2-Aminomethyl-3-(1-methyl-cyclobutyl)-propionic acid

2-Aminomethyl-3-(1-ethyl-cyclobutyl)-propionic acid

2-Aminomethyl-3-(1-propyl-cyclobutyl)-propionic acid

2-Aminomethyl-3-(1-methyl-cyclopentyl)-propionic acid

2-Aminomethyl-3-(1-ethyl-cyclopentyl)-propionic acid

2-Aminomethyl-3-(1-propyl-cyclopentyl)-propionic acid

2-Aminomethyl-3-(1-methyl-cyclohexyl)-propionic acid

2-Aminomethyl-3-(1-ethyl-cyclohexyl)-propionic acid

2-Aminomethyl-3-(1-propyl-cyclohexyl)-propionic acid

2-Aminomethyl-4-ethyl-hexanoic acid

2-Aminomethyl-4-ethyl-5-methyl-hexanoic acid

2-Aminomethyl-4-ethyl-heptanoic acid

2-Aminomethyl-4ethyl-6-methyl-heptanoic acid

2-Aminomethyl-4-ethyl-octanoic acid

2-Aminomethyl-4-ethyl-7-methyl-octanoic acid

2-Aminomethyl-4-ethyl-nonanoic acid

2-Aminomethyl-4-ethyl-8-methyl-nonanoic acid

2-Aminomethyl-4,4-dimethyl-heptanoic acid

2-Aminomethyl-4,4,8-trimethyl-nonanoic acid

2-Aminomethyl-5-ethyl-heptanoic acid

2-Aminomethyl-5-ethyl-6-methyl-heptanoic acid

2-Aminomethyl-7-cyclopropyl-5-ethyl-heptanoic acid

2-Aminomethyl-7-cyclobutyl-5-ethyl-heptanoic acid

2-Aminomethyl-7-cyclopentyl-5-ethyl-heptanoic acid

2-Aminomethyl-7-cyclohexyl-5-ethyl-heptanoic acid

2-Aminomethyl-5-ethyl-octanoic acid

2-Aminomethyl-5-ethyl-7-methyl-octanoic acid

2-Aminomethyl-5-ethyl-nonanoic acid

2-Aminomethyl-5-ethyl-8-methyl-nonanoic acid

2-Aminomethyl-4-cyclopropyl-butyric acid

2-Aminomethyl4-(1-methyl-cyclopropyl)-butyric acid

2-Aminomethyl4-(1-ethyl-cyclopropyl)-butyric acid

2-Aminomethyl-4-cyclobutyl-butyric acid

2-Aminomethyl-4-(1-methyl-cyclobutyl)-butyric acid

2-Aminomethyl-4-(1-ethyl-cyclobutyl)-butyric acid

2-Aminomethyl-4-cyclopentyl-butyric acid

2-Aminomethyl-4-(1-methyl-cyclopentyl)-butyric acid

2-Aminomethyl-4-(1-ethyl-cyclopentyl)-butyric acid

2-Aminomethyl-4-cyclohexyl-butyric acid

2-Aminomethyl-4-(1-methylcyclohexyl)-butyric acid

2-Aminomethyl-4-(1-ethyl-cyclohexyl)-butyric acid

(2R, 4S)-2-Aminomethyl-6-cyclopentyl-4-ethyl-hexanoic acid;

(2R, 4S)-2-Aminomethyl-6-cyclobutyl-4-ethyl-hexanoic acid; and

(2R, 4S)-2-Aminomethyl-6-cyclopropyl4-ethyl-hexanoic acid.

Other specific embodiments of this invention include the followingcompounds of the formula IIA and their pharmaceutically acceptablesalts:

2-Aminomethyl-4-methyl-hexanoic acid;

2-Aminomethyl-4-methyl-heptanoic acid;

2-Aminomethyl-4-methyl-octanoic acid;

2-Aminomethyl-4-methyl-nonanoic acid;

2-Aminomethyl-4-methyl-decanoic acid;

(2R, 4R)-2-Aminomethyl-4-methyl-hexanoic acid;

(2R, 4R)-2-Aminomethyl-4-methyl-heptanoic acid;

(2R, 4R)-2-Aminomethyl-4-methyl-octanoic acid;

(2R, 4R)-2-Aminomethyl-4-methyl-nonanoic acid;

(2R, 4R)-2-Aminomethyl-4-methyl-decanoic acid;

(2R, 4S)-2-Aminomethyl-4-methyl-hexanoic acid;

(2R, 4S)-2-Aminomethyl-4-methyl-heptanoic acid;

(2R, 4S)-2-Aminomethyl-4-methyl-octanoic acid;

(2R, 4S)-2-Aminomethyl-4-methyl-nonanoic acid;

(2R, 4S)-2-Aminomethyl4-methyl-decanoic acid;

2-Aminomethyl-5-cyclopropyl-4-methyl-pentanoic acid;

2-Aminomethyl-5-cyclobutyl-4-methyl-pentanoic acid;

2-Aminomethyl-5-cyclopentyl-4-methyl-pentanoic acid;

2-Aminomethyl-5-cyclohexyl-4-methyl-pentanoic acid;

2-Aminomethyl-6-cyclopropyl4-methyl-hexanoic acid;

2-Aminomethyl-6-cyclobutyl-4-methyl-hexanoic acid;

2-Aminomethyl-6-cyclopentyl-4-methyl-hexanoic acid;

2-Aminomethyl-6-cyclohexyl-4-methyl-hexanoic acid;

2-Aminomethyl-7-cyclopropyl-4-methyl-heptanoic acid;

2-Aminomethyl-7-cyclobutyl-4-methyl-heptanoic acid;

2-Aminomethyl-7-cyclopentyl4-methyl-heptanoic acid;

2-Aminomethyl-7-cyclohexyl-4-methyl-heptanoic acid;

2-Aminomethyl-8-cyclopropyl-4-methyl-octanoic acid;

2-Aminomethyl-8-cyclobutyl-4-methyl-octanoic acid;

2-Aminomethyl-8-cyclopentyl4-methyl-octanoic acid;

2-Aminomethyl-8-cyclohexyl-4-methyl-octanoic acid;

(2R, 4S)-2-Aminomethyl-5-cyclopropyl-4-methyl-pentanoic acid;

(2R, 4S)-2-Aminomethyl-5-cyclobutyl-4-methyl-pentanoic acid;

(2R, 4S)-2-Aminomethyl-5-cyclopentyl-4-methyl-pentanoic acid;

(2R, 4S)-2-Aminomethyl-5-cyclohexyl-4-methyl-pentanoic acid;

(2R, 4S)-2-Aminomethyl-6-cyclopropyl4-methyl-hexanoic acid;

(2R, 4S)-2-Aminomethyl-6-cyclobutyl-4-methyl-hexanoic acid;

(2R, 4S)-2-Aminomethyl-6-cyclopentyl-4-methyl-hexanoic acid;

(2R, 4S)-2-Aminomethyl-6-cyclohexyl-4-methyl-hexanoic acid;

(2R, 4S)-2-Aminomethyl-7-cyclopropyl-4-methyl-heptanoic acid;

(2R, 4S)-2-Aminomethyl-7-cyclobutyl-4-methyl-heptanoic acid;

(2R, 4S)-2-Aminomethyl-7-cyclopentyl4-methyl-heptanoic acid;

(2R, 4S)-2-Aminomethyl-7-cyclohexyl-4-methyl-heptanoic acid;

(2R, 4S)-2-Aminomethyl-8-cyclopropyl-4-methyl-octanoic acid;

(2R, 4S)-2-Aminomethyl-8-cyclobutyl-4-methyl-octanoic acid;

(2R, 4S)-2-Aminomethyl-8-cyclopentyl-4-methyl-octanoic acid;

(2R, 4S)-2-Aminomethyl-8-cyclohexyl4-methyl-octanoic acid;

(2R, 4R)-2-Aminomethyl-5-cyclopropyl4-methyl-pentanoic acid;

(2R, 4R)-2-Aminomethyl-5-cyclobutyl4-methyl-pentanoic acid;

(2R, 4R)-2-Aminomethyl-5-cyclopentyl-4-methyl-pentanoic acid;

(2R, 4R)-2-Aminomethyl-5-cyclohexyl-4-methyl-pentanoic acid;

(2R, 4R)-2-Aminomethyl-6-cyclopropyl-4-methyl-hexanoic acid;

(2R, 4R)-2-Aminomethyl-6-cyclobutyl-4-methyl-hexanoic acid;

(2R, 4R)-2-Aminomethyl-6-cyclopentyl-4-methyl-hexanoic acid;

(2R, 4R)-2-Aminomethyl-6-cyclohexyl4-methyl-hexanoic acid;

(2R, 4R)-2-Aminomethyl-7-cyclopropyl-4-methyl-heptanoic acid;

(2R, 4R)-2-Aminomethyl-7-cyclobutyl-4-methyl-heptanoic acid;

(2R, 4R)-2-Aminomethyl-7-cyclopentyl-4-methyl-heptanoic acid;

(2R, 4R)-2-Aminomethyl-7-cyclohexyl-4-methyl-heptanoic acid;

(2R, 4R)-2-Aminomethyl-8-cyclopropyl-4-methyl-octanoic acid;

(2R, 4R)-2-Aminomethyl-8-cyclobutyl-4-methyl-octanoic acid;

(2R, 4R)-2-Aminomethyl-8-cyclopentyl-4-methyl-octanoic acid; and

(2R, 4R)-2-Aminomethyl-8-cyclohexyl-4-methyl-octanoic acid.

This invention also relates to compounds of the formula III

and their pharmaceutically acceptable salts, wherein R₃ is defined asfor formula I above.

This invention also relates to compounds of the formula IV

and their pharmaceutically acceptable salts, wherein R₁ and R₃ aredefined as for compounds of the formula I above.

Other specific embodiments of this invention include the followingcompounds of the formula IV and their pharmaceutically acceptable salts:

2-Aminomethyl-6-cyclopropyl-5-methyl-hexanoic acid;

2-Aminomethyl-6-cyclobutyl-5-methyl-hexanoic acid;

2-Aminomethyl-6-cyclopentyl-5-methyl-hexanoic acid;

2-Aminomethyl-6-cyclohexyl-5-methyl-hexanoic acid;

2-Aminomethyl-7-cyclopropyl-5-methyl-heptanoic acid;

2-Aminomethyl-7-cyclobutyl-5-methyl-heptanoic acid;

2-Aminomethyl-7-cyclopentyl-5-methyl-heptanoic acid;

2-Aminomethyl-7-cyclohexyl-5-methyl-heptanoic acid;

2-Aminomethyl-8-cyclopropyl-5-methyl-octanoic acid;

2-Aminomethyl-8-cyclobutyl-5-methyl-octanoic acid;

2-Aminomethyl-8-cyclopentyl-5-methyl-octanoic acid;

2-Aminomethyl-8-cyclohexyl-5-methyl-octanoic acid;

2-Aminomethyl-5-methyl-heptanoic acid;

2-Aminomethyl-5-methyl-octanoic acid;

2-Aminomethyl-5-methyl-heptanoic acid;

2-Aminomethyl-5-methyl-nonanoic acid;

(2R, 6S)-2-Aminomethyl-6-cyclopropyl-5-methyl-hexanoic acid;

(2R, 6S)-2-Aminomethyl-6-cyclobutyl-5-methyl-hexanoic acid;

(2R, 6S)-2-Aminomethyl-6-cyclopentyl-5-methyl-hexanoic acid;

(2R, 6S)-2-Aminomethyl-6-cyclohexyl-5-methyl-hexanoic acid;

(2R, 6S)-2-Aminomethyl-7-cyclopropyl-5-methyl-heptanoic acid;

(2R, 6S)-2-Aminomethyl-7-cyclobutyl-5-methyl-heptanoic acid;

(2R, 6S)-2-Aminomethyl-7-cyclopentyl-5-methyl-heptanoic acid;

(2R, 6S)-2-Aminomethyl-7-cyclohexyl-5-methyl-heptanoic acid;

(2R, 6S)-2-Aminomethyl-8-cyclopropyl-5-methyl-octanoic acid;

(2R, 6S)-2-Aminomethyl-8-cyclobutyl-5-methyl-octanoic acid;

(2R, 6S)-2-Aminomethyl-8-cyclopentyl-5-methyl-octanoic acid;

(2R, 6S)-2-Aminomethyl-8-cyclohexyl-5-methyl-octanoic acid;

(2R, 6S)-2-Aminomethyl-5-methyl-heptanoic acid;

(2R, 6S)-2-Aminomethyl-5-methyl-octanoic acid;

(2R, 6S)-2-Aminomethyl-5-methyl-heptanoic acid;

(2R, 6S)-2-Aminomethyl-5-methyl-nonanoic acid;

(2R, 6R)-2-Aminomethyl-6-cyclopropyl-5-methyl-hexanoic acid;

(2R, 6R)-2-Aminomethyl-6-cyclobutyl-5-methyl-hexanoic acid;

(2R, 6R)-2-Aminomethyl-6-cyclopentyl-5-methyl-hexanoic acid;

(2R, 6R)-2-Aminomethyl-6-cyclohexyl-5-methyl-hexanoic acid;

(2R, 6R)-2-Aminomethyl-7-cyclopropyl-5-methyl-heptanoic acid;

(2R, 6R)-2-Aminomethyl-7-cyclobutyl-5-methyl-heptanoic acid;

(2R, 6R)-2-Aminomethyl-7-cyclopentyl-5-methyl-heptanoic acid;

(2R, 6R)-2-Aminomethyl-7-cyclohexyl-5-methyl-heptanoic acid;

(2R, 6R)-2-Aminomethyl-8-cyclopropyl-5-methyl-octanoic acid;

(2R, 6R)-2-Aminomethyl-8-cyclobutyl-5-methyl-octanoic acid;

(2R, 6R)-2-Aminomethyl-8-cyclopentyl-5-methyl-octanoic acid;

(2R, 6R)-2-Aminomethyl-8-cyclohexyl-5-methyl-octanoic acid;

(2R, 6R)-2-Aminomethyl-5-methyl-heptanoic acid;

(2R, 6R)-2-Aminomethyl-5-methyl-octanoic acid;

(2R, 6R)-2-Aminomethyl-5-methyl-heptanoic acid; and

(2R, 6R)-2-Aminomethyl-5-methyl-nonanoic acid.

This invention also relates to a pharmaceutical composition comprising atherapeutically effective amount of a compound of the formula I, IA,IA-1, IA-2, IB, IC, II, IIA, III, or IV, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier.

This invention also relates to a method of treating a disorder orcondition selected from epilepsy, faintness attacks, fibromyalgia,hypokinesia, cranial disorders, hot flashes, essential tremor, chemicaldependencies and addictions, (e.g., dependencies on or addictions toalcohol, amphetamines (or amphetamine-like substances) caffeine,cannabis, cocaine, heroin, hallucinogens, tobacco, inhalants and aerosolpropellants, nicotine, opioids, phenylglycidine derivatives, sedatives,hypnotics, benzodiazepines and other anxiolytics), and withdrawalsymptoms associated with such depencies or addictions, addictivebehaviors such as gambling; migraine, spasticity, arthritis, irritablebowel syndrome (IBS), chronic pain, acute pain, neuropathic pain,vascular headache, sinus headache, inflammatory disorders (e.g.,rheumatoid arthritis, osteoarthritis, psoriasis) diuresis, premenstrualsyndrome, premenstrual dysphoric disorder, tinnitis, and gastric damagein a mammal, including a human, comprising administering to a mammal inneed of such treatment a therapeutically effective amount of a compoundof the formula 1, IA, IA-1, IA-2, IB, IC, II, IIA, III, or IV, or apharmaceutically acceptable salt thereof.

The present invention also covers treating neurodegenerative disorderstermed acute brain injury. These include but are not limited to: stroke,head trauma, and asphyxia.

Stroke refers to a cerebral vascular disease and may also be referred toas a cerebral vascular incident (CVA) and includes acute thromboembolicstroke. Stroke includes both focal and global ischemia. Also, includedare transient cerebral ischemic attacks and other cerebral vascularproblems accompanied by cerebral ischemia, such as those that occur inpatients undergoing carotid endarterectomy or other cerebrovascular orvascular surgical procedures, or diagnostic vascular proceduresincluding cerebral angiography and the like.

Compounds of the formulas 1, IA, IA-1, IA-2, IB, IC, II, IIA, III, andIV, are also useful in the treatment of head trauma, spinal cord trauma,or injury from general anoxia, hypoxia, hypoglycemia, hypotension aswell as similar injuries seen during procedures from embole,hyperfusion, and hypoxia. They are also useful in preventing neuronaldamage that occurs during cardiac bypass surgery, in incidents ofintracranial hemorrhage, in perinatal asphyxia, in cardiac arrest, andstatus epilepticus.

This invention also relates to a method of treating a disorder orcondition selected from the group consisting of delerium, dementia, andamnestic and other cognitive or neurodegenerative disorders, such asParkinson's disease (PD), Huntington's disease (HD), Alzheimer'sdisease, senile dementia, dementia of the Alzheimer's type, memorydisorder, vascular dementia, and other dementias, for example, due toHIV disease, head trauma, Parkinson's disease, Huntington's disease,Pick's disease, Creutzfeldt-Jakob disease, or due to multipleaetiologies; movement disorders such as akinesias, dyskinesias,including familial paroxysmal dyskinesias, spasticities, Tourette'ssyndrome, Scott syndrome, PALSYS and akinetic-rigid syndrome;extra-pyramidal movement disorders such as medication-induced movementdisorders, for example, neuroleptic-induced Parkinsonism, neurolepticmalignant syndrome, neuroleptic-induced acute dystonia,neuroleptic-induced acute akathisia, neuroleptic-induced tardivedyskinesia and medication-induced postural tremour; Down's syndrome;demyelinating diseases such as multiple sclerosis (MS) and amylolateralsclerosis (ALS), peripheral neuropathy, for example diabetic andchemotherapy-induced-neuropathy, and postherpetic neuralgia, trigeminalneuralgia, segmental or intercostal neuralgia and other neuralgias; andcerebral vascular disorders due to acute or chronic cerebrovasculardamage such as cerebral infarction, subarachnoid haemorrhage or cerebraloedema in a mammal, including a human, comprising administering to saidmammal an amount of a compound of the formula 1, IA, IA-1, IA-2, IB, IC,II, IIA, III, or IV, or a pharmaceutically acceptable salt thereof, thatis effective in treating such disorder or condition.

Pain refers to acute as well as chronic pain. Acute pain is usuallyshort-lived and is associated with hyperactivity of the sympatheticnervous system. Examples are postoperative pain and allodynia. Chronicpain is usually defined as pain persisting from 3 to 6 months andincludes somatogenic pain and psychogenic pain. Other pain isnociceptive.

Examples of the types of pain that can be treated with the compounds offormulas 1, IA, IA-1, IA-2, IB, IC, II, IIA, III, and IV of the presentinvention and their pharmaceutically acceptable salts include painresulting from soft tissue and peripheral damage, such as acute trauma,pain associated with osteoarthritis and rheumatoid arthritis,musculo-skeletal pain, such as pain experienced after trauma; spinalpain, dental pain, myofascial pain syndromes, episiotomy pain, and painresulting from bums; deep and visceral pain, such as heart pain, musclepain, eye pain, orofacial pain, for example, odontalgia, abdominal pain,gynaecological pain, for example, dysmenorrhoea, labour pain and painassociated with endometriosis; pain associated with nerve and rootdamage, such as pain associated with peripheral nerve disorders, forexample, nerve entrapment and brachial plexus avulsions, amputation,peripheral neuropathies, tic douloureux, atypical facial pain, nerveroot damage, trigeminal neuralgia, neuropathic lower back pain, HIVrelated neuropathic pain, cancer related neuropathic pain, diabeticneuropathic pain, and arachnoiditis; neuropathic and non-neuropathicpain associated with carcinoma, often referred to as cancer pain;central nervous system pain, such as pain due to spinal cord or brainstem damage; lower back pain; sciatica; phantom limb pain, headache,including migraine and other vascular headaches, acute or chronictension headache, cluster headache, temperomandibular pain and maxillarysinus pain; pain resulting from ankylosing spondylitis and gout; paincaused by increased blader contractions; post operative pain; scar pain;and chronic non-neuropathic pain such as pain associated withfibromyalgia, HIV, rheumatoid and osteoarthritis, anthralgia andmyalgia, sprains, strains and trauma such as broken bones; and postsurgical pain.

Still other pain is caused by injury or infection of peripheral sensorynerves. It includes, but is not limited to pain from peripheral nervetrauma, herpes virus infection, diabetes mellitus, fibromyalgia,causalgia, plexus avulsion, neuroma, limb amputation, and vasculitis.Neuropathic pain is also caused by nerve damage from chronic alcoholism,human immunodeficiency virus infection, hypothyroidism, uremia, orvitamin deficiencies. Neuropathic pain includes, but is not limited topain caused by nerve injury such as, for example, the pain diabeticssuffer from.

Psychogenic pain is that which occurs without an organic origin such aslow back pain, atypical facial pain, and chronic headache.

Other types of pain are: inflammatory pain, osteoarthritic pain,trigeminal neuralgia, cancer pain, diabetic neuropathy, restless legsyndrome, acute herpetic and postherpetic neuralgia, causalgia, brachialplexus avulsion, occipital neuralgia, gout, phantom limb, burn, andother forms of neuralgia, neuropathic and idiopathic pain syndrome.

The compounds of the invention are also useful in the treatment ofdepression. Depression can be the result of organic disease, secondaryto stress associated with personal loss, or idiopathic in origin. Thereis a strong tendency for familial occurrence of some forms of depressionsuggesting a mechanistic cause for at least some forms of depression.The diagnosis of depression is made primarily by quantification ofalterations in patients' mood. These evaluations of mood are generallyperformed by a physician or quantified by a neuropsychologist usingvalidated rating scales, such as the Hamilton Depression Rating Scale orthe Brief Psychiatric Rating Scale. Numerous other scales have beendeveloped to quantify and measure the degree of mood alterations inpatients with depression, such as insomnia, difficulty withconcentration, lack of energy, feelings of worthlessness, and guilt. Thestandards for diagnosis of depression as well as all psychiatricdiagnoses are collected in the Diagnostic and Statistical Manual ofMental Disorders (Fourth Edition) referred to as the DSM-IV-R manualpublished by the American Psychiatric Association, 1994.

This invention also relates to a method of treating a disorder orcondition selected from the group consisting of mood disorders, such asdepression, or more particularly, depressive disorders, for example,single episodic or recurrent major depressive disorders, dysthymicdisorders, depressive neurosis and neurotic depression, melancholicdepression, including anorexia, weight loss, insomnia, early morningwaking and psychomotor retardation, atypical depression (or reactivedepression), including increased appetite, hypersomnia, psychomotoragitation or irritability, seasonal affective disorder and pediatricdepression; or bipolar disorders or manic depression, for example,bipolar I disorder, bipolar II disorder and cyclothymic disorder;conduct disorder and disruptive behavior disorder; anxiety disorders,such as panic disorder with or without agoraphobia, agoraphobia withouthistory of panic disorder, specific phobias, for example, specificanimal phobias, social anxiety, social phobia, obsessive-compulsivedisorder, stress disorders, including post-traumatic stress disorder andacute stress disorder, and generalized anxiety disorders; borderlinepersonality disorder; schizophrenia and other psychotic disorders, forexample, schizophreniform disorders, schizoaffective disorders,delusional disorders, brief psychotic disorders, shared psychoticdisorders, psychotic disorders with delusions or hallucinations,psychotic episodes of anxiety, anxiety associated with psychosis,psychotic mood disorders such as severe major depressive disorder; mooddisorders associated with psychotic disorders such as acute mania anddepression associated with bipolar disorder, mood disorders associatedwith schizophrenia; behavioral disturbances associated with mentalretardation, autistic disorder, and conduct disorder in a mammal,including a human, comprising administering to said mammal an amount ofa compound of the formula 1, IA, IA-1, IA-2, IB, IC, II, IIA, III, orIV, or a pharmaceutically acceptable salt thereof, that is effective intreating such disorder or condition.

The compounds of the invention are also useful in the treatment of sleepdisorders. Sleep disorders are disturbances that affect the ability tofall and/or stay asleep, that involves sleeping too much, or that resultin abnormal behavior associated with sleep. The disorders include, forexample, insomnia, drug-associated sleeplessness, hypersomnia,narcolepsy, sleep apnea syndromes, and parasomnias.

This invention also relates to a method of treating a disorder orcondition selected from the group consisting of sleep disorders (e.g.,insomnia, drug-associated sleeplessness, REM sleep disorders,hypersomnia, narcolepsy, sleep-wake cycle disorders, sleep apneasyndromes, parasomnias, and sleep disorders associated with shift workand irregular work hours) a mammal, including a human, comprisingadministering to said mammal an amount of a compound of the formula I,IA, IA-1, IA-2, IB, IC, II, IIA, III, or IV, or a pharmaceuticallyacceptable salt thereof, that is effective in treating such disorder orcondition.

Compounds of formulas 1, IA, IA-1, IA-2, IB, IC, II, IIA, III, and IVcontain at least one chiral center and therefore may exist in differentenantiomeric and diastereomeric forms. This invention relates to alloptical isomers and all stereoisomers of compounds of the formulas I,IA, IA-1, IA-2, IB, IC, II, IIA, III, and IV, both as racemic mixturesand as individual enantiomers and diastereoisomers of such compounds,and mixtures thereof, and to all pharmaceutical compositions and methodsof treatment defined above that contain or employ them, respectively.Individual isomers can be obtained by known methods, such as opticalresolution, optically selective reaction, or chromatographic separationin the preparation of the final product or its intermediate. Individualenantiomers of the compounds of this invention may have advantages, ascompared with the racemic mixtures of these compounds, in the treatmentof various disorders or conditions.

The present invention also includes isotopically labelled compounds,which are identical to those recited in formulas I, IA, IA-1, IA-2, IB,IC, II, IIA, III, and IV, but for the fact that one or more atoms arereplaced by an atom having an atomic mass or mass number different fromthe atomic mass or mass number usually found in nature. Examples ofisotopes that can be incorporated into compounds of the presentinvention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, sulfur, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹¹C,¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively.Compounds of the present invention, prodrugs thereof, andpharmaceutically acceptable salts of said compounds or of said prodrugswhich contain the aforementioned isotopes and/or other isotopes of otheratoms are within the scope of this invention. Certain isotopicallylabelled compounds of the present invention, for example those intowhich radioactive isotopes such as ³H and ¹⁴C are incorporated, areuseful in drug and/or substrate tissue distribution assays. Tritiated,i.e., ³H, and carbon-14, i.e. ¹⁴C, isotopes are particularly preferredfor their ease of preparation and detectability. Further, substitutionwith heavier isotopes such as deuterium, i.e., ²H, can afford certaintherapeutic advantages resulting from greater metabolic stability, forexample increased in vivo half-life or reduced dosage requirements and,hence, may be preferred in some circumstances. Isotopically labelledcompounds of formula I of this invention and prodrugs thereof cangenerally be prepared by carrying out the procedures disclosed in theSchemes and/or in the Examples and Preparations below, by substituting areadily available isotopically labelled reagent for a non-isotopicallylabelled reagent.

The term “alkyl”, as used herein, unless otherwise indicated, includessaturated monovalent hydrocarbon radicals having straight, branched orcyclic moieties or combinations thereof. Examples of “alkyl” groupsinclude, but are not limited to, methyl, ethyl, propyl, isopropyl,butyl, iso- sec- and tert-butyl, pentyl, hexyl, heptyl, 3-ethylbutyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbomyl,and the like.

The term “alkoxy”, as used herein, unless otherwise indicated, means“alkyl-O—”, wherein “alkyl” is as defined above. Examples of “alkoxy”groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxyand pentoxy.

The term “treating”, as used herein, refers to reversing, alleviating,inhibiting the progress of, or preventing the disorder or condition towhich such term applies, or preventing one or more symptoms of suchcondition or disorder. The term “treatment”, as used herein, refers tothe act of treating, as “treating” is defined immediately above.

Because amino acids are amphoteric, pharmacologically compatible saltscan be salts of appropriate inorganic or organic acids, for example,hydrochloric, sulphuric, phosphoric, acetic, oxalic, lactic, citric,malic, salicylic, malonic, maleic, succinic, and ascorbic. Starting fromcorresponding hydroxides or carbonates, salts with alkali metals oralkaline earth metals, for example, sodium, potassium, magnesium, orcalcium are formed. Salts with quaternary ammonium ions can also beprepared with, for example, the tetramethyl-ammonium ion.

The effectiveness of an orally administered drug is dependent upon thedrug's efficient transport across the mucosal epithelium and itsstability in entero-hepatic circulation. Drugs that are effective afterparenteral administration but less effective orally, or whose plasmahalf-life is considered too short, may be chemically modified into aprodrug form.

A prodrug is a drug that has been chemically modified and may bebiologically inactive at its site of action, but which may be degradedor modified by one or more enzymatic or other in vivo processes to theparent bioactive form.

This chemically modified drug, or prodrug, should have a differentpharmacokinetic profile than the parent drug, enabling easier absorptionacross the mucosal epithelium, better salt formulation and/orsolubility, improved systemic stability (for an increase in plasmahalf-life, for example). These chemical modifications may be

1) ester or amide derivatives which may be cleaved by, for example,esterases or lipases. For ester derivatives, the ester is derived fromthe carboxylic acid moiety of the drug molecule by known means. Foramide derivatives, the amide may be derived from the carboxylic acidmoiety or the amine moiety of the drug molecule by known means.

2) peptides which may be recognized by specific or nonspecificproteinases. A peptide may be coupled to the drug molecule via amidebond formation with the amine or carboxylic acid moiety of the drugmolecule by known means.

3) derivatives that accumulate at a site of action through membraneselection of a prodrug form or modified prodrug form,

4) any combination of 1 to 3.

Current research in animal experiments has shown that the oralabsorption of certain drugs may be increased by the preparation of“soft” quaternary salts. The quaternary salt is termed a “soft”quaternary salt since, unlike normal quaternary salts, e.g., R—N+(CH₃)₃,it can release the active drug upon hydrolysis.

“Soft” quaternary salts have useful physical properties compared withthe basic drug or its salts. Water solubility may be increased comparedwith other salts, such as the hydrochloride, but more important theremay be an increased absorption of the drug from the intestine. Increasedabsorption is probably due to the fact that the “soft” quaternary salthas surfactant properties and is capable of forming micelles andunionized ion pairs with bile acids, etc., which are able to penetratethe intestinal epithelium more effectively. The prodrug, afterabsorption, is rapidly hydrolyzed with release of the active parentdrug.

Prodrugs of compounds of formulas 1, IA, IA-1, IA-2, IB, IC, II, IIA,III, and IV are included within the scope of this invention. Prodrugsand soft drugs are known in the art (Palomino E., Drugs of the Future,1990;15(4):361-368). The last two citations are hereby incorporated byreference.

Certain of the compounds of the present invention can exist inunsolvated forms as well as solvated forms, including hydrated forms. Ingeneral, the solvated forms, including hydrated forms, are equivalent tounsolvated forms and are intended to be encompassed within the scope ofthe present invention.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of this invention can be prepared as described below. Inthe reaction schemes and discussion that follow, structural formulas 1,IA, IA-1, IA-2, IB, IC, 11, IIA, III, and IV, and the radicals R₁, R₂,R₃R₄R₅ and R6, unless otherwise indicated, are defined as above.

Diverse methods exist for the preparation of chiral and racemic β-aminoacids. Such methods can be found in “Enantioselective Synthesis ofβ-Amino Acids”, Juaristi, Eusebio; Editor. USA, 1997, Wiley-VCH, NewYork, N.Y.

The methods described below are illustrative of methods that can beutilized for the preparation of such compounds but are not limiting inscope.

According to the procedure of Lázár, et al, Synth. Commun, 1998, 28(2),219-224, compounds of the formula IA can be prepared by heating toreflux compounds of the formula 1 in a alcoholic solvent such asethanol, in the presence of malonic acid and ammonium acetate. Aldehydesof the formula 1 can be prepared from commercially available materialsusing methods well known to those of skill in the art.

Compounds that can be made by the above method include, but are notlimited to the following:

3-Amino-6-cyclopropyl-5-methyl-hexanoic acid;

3-Amino-6-cyclobutyl-5-methyl-hexanoic acid;

3-Amino-6-cyclopentyl-5-methyl-hexanoic acid;

3-Amino-6-cyclohexyl-5-methyl-hexanoic acid;

3-Amino-7-cyclopropyl-5-methyl-heptanoic acid;

3-Amino-7-cyclobutyl-5-methyl-heptanoic acid;

3-Amino-7-cyclopentyl-5-methyl-heptanoic acid;

3-Amino-7-cyclohexyl-5-methyl-heptanoic acid;

3-Amino-8-cyclopropyl-5-methyl-octanoic acid

3-Amino-8-cyclobutyl-5-methyl-octanoic acid;

3-Amino-8-cyclopentyl-5-methyl-octanoic acid;

3-Amino-8-cyclohexyl-5-methyl-octanoic acid;

3-Amino-6-cyclopropyl-5,5-dimethyl-hexanoic acid;

3-Amino-6-cyclobutyl-5,5-dimethyl-hexanoic acid;

3-Amino-6-cyclopentyl-5,5-dimethyl-hexanoic acid;

3-Amino-6-cyclohexyl-5,5-dimethyl-hexanoic acid;

3-Amino-7-cyclopropyl-5,5-dimethyl-heptanoic acid;

3-Amino-7-cyclobutyl-5,5-dimethyl-heptanoic acid;

3-Amino-7-cyclopentyl-5,5-dimethyl-heptanoic acid; and

3-Amino-7-cyclohexyl-5,5-dimethyl-heptanoic acid.

The use of chiral amine additions to α,β-unsaturated systems as asynthetic approach to β-amino acids, as illustrated in Method B above,has been described previously (see, e.g., S. G. Davies et al, J. Chem.Soc. Chem. Commun, 1153,1993; S. G. Davies, Synlett, 1994, 117; Ishikawaet al, Synlett, 1998, 1291; Hawkins, J. Org. Chem., 1985, 51, 2820).Referring to Method B above, compounds of the formula IA can be preparedfrom the corresponding compounds of the formula 7, wherein PG representsa suitable ester protecting group that can be removed by hydrolysis orhydrogenolysis, using conditions well known to those of skill in theart. (See T. W. Greene and P. G. M. Wuts., “Protective groups in organicsynthesis”, Wiley, 1991 for a detailed description for the formation andremoval of suitable protecting groups). For example, this reaction canbe conducted under hydrolytic conditions by treatment with anappropriate acid, such as hydrochloric acid or sulfuric acid, at atemperature from about room temperature to about the reflux temperatureof the reaction mixture, preferably at the reflux temperature, or bytreatment with an appropriate inorganic base, such as sodium hydroxide,potassium hydroxide, or lithium hydroxide, preferably sodium hydroxide,at a temperature from about room temperature to about the refluxtemperature, preferably at about room temperature. This reaction ispreferably carried out using hydrochloric acid at the refluxtemperature. When PG is t-butyl, however, the reaction is preferablycarried out in trifluoroacetic acid (TFA). When PG is a basic group, thehydrolysis can be carried out under basic conditions, using methods wellknown to those of skill in the art, for example, using sodium orpotassium hydroxide.

Compounds of the formula 7 can be prepared from the correspondingcompounds of the formula 6 using hydrogenolysis conditions that are wellknown to those of skill in the art. For example, this reaction can becarried out by treating the compounds of formula 6 with a palladiummetal catalyst, such as, for example, palladium hydroxide on carbon, orpalladium on carbon, or with Raney Nickel, in a solvent such as, forexample, methanol, ethanol or tetrahydrofuran, under an atmosphere ofhydrogen (between about 1 and 5 atmospheres of pressure) to give thedesired compound of formula 7. Preferably, the reaction is carried outusing palladium on carbon in ethanol under about 1 atmosphere ofhydrogen.

Compounds of the formula 6 can be prepared by treating the correspondingcompounds of formula 4 with an appropriate amine such as(R)-(+)-N-benzyl-α-methylbenzylamine,(S)-(-)-N-benzyl-α-methylbenzylamine after treatment with an appropriatebase such as lithium diisopropylamide, n-butyl lithium, or lithium orpotassium bis(trimethylsilyl)amide, in a solvent such as ethyl ether,or, preferably, tetrahydrofuran (THF), at a temperature from about −80°C. to about 25° C., and then adding the appropriate compound of formulaformula 4. The stereochemistry about the nitrogen of the amine willdetermine the stereochemistry about the nitrogen of the final product.Preferably, this reaction is carried out using either(R)-(+)-N-benzyl-α-methylbenzylamine,(S)-(-)-N-benzyl-α-methylbenzylamine, after deprotonation withn-butyl-lithium in tetrahydrofuran, at a temperature of about −78° C.,according to method described by Bull, Steven D.; Davies, Stephen G.;and Smith, Andrew D, J. Chem. Soc., Perkin Trans. 1, 2001, 22,2931-2938. Preferably, this reaction is carried out using either(R)-(+)-N-benzyl-α-methylbenzylamine, or(S)-(−)-N-benzyl-α-methylbenzylamine, after deprotonation withn-butyl-lithium in tetrahydrofuran, at a temperature of about −78° C.,according to method described by Bull, Steven D.; Davies, Stephen G.;and Smith, Andrew D, J. Chem. Soc., Perkin Trans. 1, 2001, 22,2931-2938.

Compounds of the formula 4 can be prepared from the correspondingcompounds of formula 3 by treating them with an appropriate phosphonateester in the presence of a suitable base such as sodium hydride, lithiumdiisopropylamide, or triethyl amine and either lithium chloride orlithium bromide, in a solvent such as ether or THF. Preferably, thecompound of formula 3 is reacted with a phosphonate ester (ALK=methyl,ethyl, isopropyl, benzyl or the like) in the presence of lithium bromideand triethylamine in tetrahydrofuran at about room temperature.Compounds of the formula 3 can be prepared from commercially availablematerials using methods well known to those of skill in the art. It willbe appreciated that compounds of the formula 3 may possess one or morestereogenic centers. Using the above described method, compounds withspecific stereochemical configurations can be prepared.

Compounds that can be made by this method include, but are not limitedto the following:

(3S,5R)-3-Amino-6-cyclopropyl-5-methyl-hexanoic acid;

(3S,5R)-3-Amino-6-cyclobutyl-5-methyl-hexanoic acid;

(3S,5R)-3-Amino-6-cyclopentyl-5-methyl-hexanoic acid;

(3S,5R)-3-Amino-6-cyclohexyl-5-methyl-hexanoic acid;

(3S,5R)-3-Amino-8-cyclopropyl-5-methyl-octanoic acid;

(3S,5R)-3-Amino-8-cyclobutyl-5-methyl-octanoic acid;

(3S,5R)-3-Amino-8-cyclopentyl-5-methyl-octanoic acid;

(3S,5R)-3-Amino-8-cyclohexyl-5-methyl-octanoic acid;

(3S,5S)-3-Amino-6-cyclopropyl-5-methyl-hexanoic acid;

(3S,5S)-3-Amino-6-cyclobutyl-5-methyl-hexanoic acid;

(3S,5S)-3-Amino-6-cyclopentyl-5-methyl-hexanoic acid;

(3S,5S)-3-Amino-6-cyclohexyl-5-methyl-hexanoic acid;

(3S,5S)-3-Amino-8-cyclopropyl-5-methyl-octanoic acid;

(3S,5S)-3-Amino-8-cyclobutyl-5-methyl-octanoic acid;

(3S,5S)-3-Amino8-cyclopentyl-5-methyl-octanoic acid;

(3S,5S)-3-Amino-8-cyclohexyl-5-methyl-octanoic acid;

(3S)-3-Amino-6-cyclopropyl-5,5-dimethyl-hexanoic acid;

(3S)-3-Amino-6-cyclobutyl-5,5-dimethyl-hexanoic acid;

(3S)-3-Amino-6-cyclopentyl-5,5-dimethyl-hexanoic acid;

(3S)-3-Amino-6-cyclohexyl-5,5-dimethyl-hexanoic acid;

(3S)-3-Amino-7-cyclopropyl-5,5-dimethyl-heptanoic acid;

(3S)-3-Amino-7-cyclobutyl-5,5-dimethyl-heptanoic acid;

(3S)-3-Amino-7-cyclopentyl-5,5-dimethyl-heptanoic acid; and

(3S)-3-Amino-7-cyclohexyl-5,5-dimethyl-heptanoic acid.

The diastereoalkylation of imides such as those of formula 10 to affordchiral succinate analogs such as those of formula 11 has been previouslydescribed as an approach to preparing β-amino acids (see, e.g., Evans etal, J. Org. Chem., 1999, 64, 6411; Sibi and Deshpande, J. Chem. Soc.Perkin Trans 1., 2000, 1461; Arvanitis et al, J. Chem. Soc. Perkin Trans1., 1998, 521).

Compounds of structure 11 can be prepared from compounds of structure 10in the presence of a suitably derived ester (PG as defined above, LG=Bror I or Cl) such as, for example, t-butyl bromoacetate, benzylbromoacetate with an organometallic base such as, for example, lithiumdiisopropylamide or lithium bis(trimethylsilyl)amide or sodiumbis(trimethylsilyl)amide and the like in a solvent such as, for example,tetrahydrofuran, ether, and the like. The reaction can be carried outusing sodium bis(trimethylsilyl)amide in tetrahydrofuran at −78° C. andtreatment of the resultant anion intermediate with t-butyl bromoacetateat −78° C. to −30° C.

Compounds of the formula 12 can be prepared by hydrolysing thecorresponding compounds of formula 11 in the presence of lithiumhydroxide and hydrogen peroxide in a solvent such as water or THF, at atemperature from about 0° C. to about room temperature. Preferably, thisreaction is carried out using hydrogen peroxide and lithium hydroxide inaqueous tetrahydrofuran at about 0° C. according to the method describedin the literature (See Yuen P -W., Kanter G. D., Taylor C. P., andVartanian M. G., Bioorganic and Medicinal Chem. Lett.,1994;4(6):823-826).

Treatment of a compound of the formula 12 with diphenylphosphorylazidein the presence of a suitable alcohol such as t-butanol, benzyl alcoholor p-methoxybenzyl alcohol, in a suitable solvent such as toluene,benzene, or THF, at a temperature from about 50° C. to about the refluxtemperature of the reaction mixture yields the corresponding compound offormula 13 wherein R₅ is methyl, ethyl, t-butyl, benzyl, orp-methoxybenzyl. R₅ is dependent on the choice of the alcohol used.Preferably, this reaction is carried out using a toluene solvent in thepresence of p-methoxybenzyl alcohol under refluxing conditions.

Compounds of the formula 13 can be converted into the desired compoundsof formula IA by hydrolysis or hydrogenolysis, using conditions wellknown to those of skill in the art. (See T. W. Greene and P. G. M.Wuts., unprotected groups in organic synthesis, Wiley, 1991 for adetailed description for the formation and removal of suitableprotecting groups). For example, this reaction can be conducted underhydrolytic conditions by treatment with an appropriate acid, such ashydrochloric acid or sulfuric acid, at a temperature from about roomtemperature to about the reflux temperature of the reaction mixture,preferably at the reflux temperature, or by treatment with anappropriate inorganic base, such as sodium hydroxide, potassiumhydroxide, or lithium hydroxide, preferably sodium hydroxide, at atemperature from about room temperature to about the reflux temperature,preferably at about room temperature. This reaction is preferablycarried out using hydrochloric acid at the reflux temperature. When PGis t-butyl, however, the reaction is preferably carried out intrifluoroacetic acid (TFA). When PG is a basic group, the hydrolysis canbe carried out under basic conditions, using methods well known to thoseof skill in the art, for example, using sodium or potassium hydroxide.

Compounds of the formula 10 can be prepared by treating thecorresponding compounds of formula 8 with an amine base such astriethylamine, in the presence of trimethylacetylchloride, in anethereal solvent such as THF, and then treating the intermediates formedby this reaction [in situ] with a chiral oxazolidinone of the formula 9.Examples of other oxazolidonones that can be used in this method are:(4S)-(−)4-isopropyl-2-oxazolidinone; (S)-(−)-4-benzyl-2-oxazolidinone;(4S,5R)-(−)-4-methyl-5-phenyl-2-oxazolidinone;(R)-(+)-4-benzyl-2-oxazolidinone, (S)-(+)-4-phenyl-2-oxazolidinone;(R)-(−)-4-phenyl-2-oxazolidinone; (R)-4-isopropyl-2-oxazolidinone; and(4R,5S)-(+)-4-methyl-5-phenyl-2-oxazolidinone)) and lithium chloride.Preferably, this reaction is carried out by treating an acid of theformula 8 with trimethylacetylchloride and triethylamine intetrahydrofuran at about −20° C., followed by treatment of theintermediate formed in such reaction with an oxazolidinone of theformula 9 and lithium chloride at about room temperature according toliterature procedures (See Ho G -J. and Mathre D. J., J. Org. Chem.,1995;60:2271 -2273).

Alternatively, compounds of the formula 10 can be prepared by treatingthe corresponding compounds of the formula 9 with the acid chloridederived from treatment of the corresponding compound of the formula 8with oxalyl chloride, in a solvent such as dichloromethane, in thepresence of dimethylformamide (DMF). Acids of the formula 8 can beprepared from commercially available materials using methods well knownto those of skill in the art. These acids may possess one or more chiralcenters. The use of citronellyl bromide and citronellol in the synthesisof such acids is described in Examples 1, 2 and 3 of this application.

Compounds that can be prepared by the above Method C include, but arenot limited to the following:

(3S,5R)-3-Amino-5-methyl-heptanoic acid;

(3S,5R)-3-Amino-5-methyl-octanoic acid;

(3S,5R)-3-Amino-5-methyl-nonanoic acid;

(3S,5R)-3-Amino-5-methyl-decanoic acid;

(3S,5S)-3-Amino-5-methyl-heptanoic acid;

(3S,5S)-3-Amino-5-methyl-octanoic acid;

(3S,5S)-3-Amino-5-methyl-nonanoic acid;

(3S,5S)-3-Amino-5-methyl-decanoic acid;

(3S)-3-Amino-5,5 -dimethyl-heptanoic acid;

(3S)-3-Amino-5,5-dimethyl-octanoic acid;

(3S)-3-Amino-5,5-dimethyl-nonanoic acid;

(3S)-3-Amino-5,5-dimethyl-decanoic acid;

(3S,5R)-3-Amino-7-cyclopropyl-5-methyl-heptanoic acid;

(3S,5R)-3-Amino-7-cyclobutyl-5-methyl-heptanoic acid;

(3S,5R)-3-Amino-7-cyclopentyl-5-methyl-heptanoic acid;

(3S,5R)-3-Amino-7-cyclohexyl-5-methyl-heptanoic acid;

(3S,5S)-3-Amino-7-cyclopropyl-5-methyl-heptanoic acid;

(3S,5S)-3-Amino-7-cyclobutyl-5-methyl-heptanoic acid;

(3S,5S)-3-Amino-7-cyclopentyl-5-methyl-heptanoic acid; and

(3S,5S)-3-Amino-7-cyclohexyl-5-methyl-heptanoic acid.

Alternatively, referring to the reaction scheme (Method D) below,compounds of the formula 11 can be treated with an appropriate acid (forexample, trifluoroacetic acid (TFA) when the t-butyl ester is used) toyield the corresponding compounds of formula 14, which can then besubjected to a Curtius rearrangement (where R₅ is defined as above) toyield the corresponding compounds of formula 15 (See Arvanitis et al, J.Chem. Soc. Perkin Trans 1., 1998, 521 for a description of thisapproach). Further hydrolysis of the imide group (to yield thecorresponding compound of formula 16) and the carbamate group gives thedesired β-amino acids of formula II.

Compound 16 can be derived from compound 15 as described above for theconversion of compounds of the formula 11 into compounds of the formula12. Compounds of the formula 17 can be prepared from correspondingcompounds of the formula 16 through treatment with a strong acid, suchas hydrochloric acid or the like, or a strong base, such as sodium orpotassium hydroxide or, if R₅ is benzyl or p-methoxybenzyl, throughhygrogenolytic conditions, using palladium on carbon in ethanol or THFunder a hydrogen atmosphere. This approach, which preserves thestereochemistry about the chiral center in the compounds of formula 11,which is also present in the product of formula 11, is described inExample 4 of this application.

Compounds that can be made by this method include, but are not limitedto the following:

(2R, 4R)-2-Aminomethyl-4-methyl-hexanoic acid;

(2R, 4R)-2-Aminomethyl-4-methyl-heptanoic acid;

(2R, 4R)-2-Aminomethyl-4-methyl-octanoic acid;

(2R, 4R)-2-Aminomethyl-4-methyl-nonanoic acid;

(2R, 4R)-2-Aminomethyl-4-methyl-decanoic acid;

(2R, 4S)-2-Aminomethyl-4-methyl-hexanoic acid;

(2R, 4S)-2-Aminomethyl-4-methyl-heptanoic acid;

(2R, 4S)-2-Aminomethyl4-methyl-octanoic acid;

(2R, 4S)-2-Aminomethyl-4-methyl-nonanoic acid;

(2R, 4S)-2-Aminomethyl-4-methyl-decanoic acid;

(2R, 4S)-2-Aminomethyl-6-cyclopropyl-4-methyl-hexanoic acid;

(2R, 4S)-2-Aminomethyl-6-cyclobutyl-4-methyl-hexanoic acid;

(2R, 4S)-2-Aminomethyl-6-cyclopentyl-4-methyl-hexanoic acid; and

(2R, 4S)-2-Aminomethyl-6-cyclohexyl-4-methyl-hexanoic acid;

Other alternative approaches to synthesizing α-substituted β-amino acidsthat can be utilized for preparing the compounds of this inventioninclude those described by Juaristi et al Tetrahedron Asymm., 7, (8),1996, 2233 and Seebach et al, Eur. J. Org. Chem., 1999, 335, or byArvanitis et al, J. Chem. Soc. Perkin Trans 1., 1998, 521, as shown inMethod E below:

Method F below illustrates an alternate method of preparing compounds ofthe formula II.

According to the procedure disclosed by Hoffmann-La Roche (FR 137773619641106), compounds of formula 3 can be prepared from unsaturatedcyanoesters of formula 2 by reduction and hydrolysis. In turn,cyanoesters 2 can be prepared via Knoevenagel condensation of aldehydes1 with cyanoacetic esters (e.g. Paine, J. B.; Woodward, R. B.; Dolphin,D., J. Org. Chem. 1976, 41, 2826). Aldehydes of the formula 1 can beprepared from commercially available materials by methods known to thoseskilled in the art.

Compounds of the formulas III and IV can be prepared using proceduresanalogous to those of Method F that will be obvious to those of skill inthe art. When synthesizing a compound of the formula III, the startingmaterial should be a compound similar to formula 1 in Method F, butwherein the hydrogen attached to the carbonyl group in formula 1 isreplaced by a methyl group.

The use of chiral imines to afford β-amino acids, as illustrated inMethod G below, has been described previously (see, e.g Tang, T. P.;Ellman, J. A. J. Org. Chem. 1999, 64, 12-13.).

The final step in the above scheme is a hydrolysis of both thesulfonamide and ester groups. This reaction is generally carried outusing a strong acid such as hydrochloric acid, hydrobromic acid orsulfuric acid, in a solvent such as water or dioxane or a mixture ofwater and dioxane, at a temperature from about 20° C. to about 50° C.,preferably at about room temperature.

The preparation of compounds of this invention that are not specificallydescribed in the foregoing experimental section can be accomplishedusing combinations of the reactions described above that will beapparent to those skilled in the art.

In each of the reactions discussed or illustrated above, pressure is notcritical unless otherwise indicated. Pressures from about 0.5atmospheres to about 5 atmospheres are generally acceptable, and ambientpressure, i.e., about 1 atmosphere, is preferred as a matter ofconvenience.

The compounds of the formula 1 and the Group A compounds, and theintermediates shown in the above reaction schemes can be isolated andpurified by conventional procedures, such as recrystallization orchromatographic separation.

The ability of compounds of the present invention to bind to theα2δ-subunit of a calcium channel can be determined using the followingbinding assay.

The radioligand binding assay using [³H]-gabapentin and the α2δ subunitderived from porcine brain tissue was used (See, Gee, Nicolas S et al.“The novel anticonvulsant drug, gabapentin (Neurontin), binds to the α2δsubunit of a calcium channel” J. Biol. Chem. (1996), 271(10), 5768-76).Compounds of the invention bind with nanomolar to micromolar affinityfor the α2δ protein. For example, R-3-amino-5,9-dimethyl-decanoic acidbinds with 527 nM affinity to the α2δ protein, (3S,5S)-3-amino-5-methyl-octanoic acid binds with 1 uM affinity, (2R,4R)-2-Aminomethyl-4-methyl-heptanoic acid binds with 29 nM affinity,2-Aminomethyl-4,4-dimethyl-heptanoic acid binds with 83 nM affinity.

The In vivo activity of compounds of this invention can be determined inanimal models of hyperalgesia (See Sluka, K., et al. 2001, “UnilateralIntramuscular Injections Of Acidic Saline Produce A Bilateral,Long-Lasting Hyperalgesia”, Muscle Nerve 24: 3746; Dixon, W., 1980,“Efficient analysis of experimental observations”. Ann Rev PharmacolToxicol 20:441-462; Randall L. O. and Selitto J. J., “A Method ForMeasurement Of Analgesic Activity On Inflamed Tissue,” Arch. Int.Pharmacodyn, 1957;4:409419; Hargreaves K., Dubner R., Brown F., FloresC., and Joris J. “A New And Sensitive Method For Measuring ThermalNociception In Cutaneous Hyperalgesia”. Pain. 32:77-88, 1988.), anxiety(Vogel J R, Beer B, and Clody D E, “A Simple And Reliable ConflictProcedure For Testing Anti-Anxiety Agents”, Psychophannacologia 21:1-7,1971),

The compounds of the present invention, and their pharmaceuticallyacceptable salts, can be administered to mammals via either the oral,parenteral (such as subcutaneous, intravenous, intramuscular,intrasternal and infusion techniques), rectal, buccal or intranasalroutes.

The novel compounds of the present invention may be administered aloneor in combination with pharmaceutically acceptable carriers or diluentsby any of the routes previously indicated, and such administration maybe carried out in single or multiple doses. More particularly, the noveltherapeutic agents of this invention can be administered in a widevariety of different dosage forms, i.e., they may be combined withvarious pharmaceutically acceptable inert carriers in the form oftablets, capsules, lozenges, troches, hard candies, suppositories,jellies, gels, pastes, ointments, aqueous suspensions, injectablesolutions, elixirs, syrups, and the like. Such carriers include soliddiluents or fillers, sterile aqueous media and various non-toxic organicsolvents, etc. Moreover, oral pharmaceutical compositions can besuitably sweetened and/or flavored. In general, the weight ratio of thenovel compounds of this invention to the pharmaceutically acceptablecarrier will be in the range from about 1:6 to about 2:1, and preferablyfrom about 1:4 to about 1:1.

For oral administration, tablets containing various excipients such asmicrocrystalline cellulose, sodium citrate, calcium carbonate, dicalciumphosphate and glycine may be employed along with various disintegrantssuch as starch (and preferably corn, potato or tapioca starch), alginicacid and certain complex silicates, together with granulation binderslike polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally,lubricating agents such as magnesium stearate, sodium lauryl sulfate andtalc are often very useful for tabletting purposes. Solid compositionsof a similar type may also be employed as fillers in gelatin capsules;preferred materials in this connection also include lactose or milksugar as well as high molecular weight polyethylene glycols. Whenaqueous suspensions and/or elixirs are desired for oral administration,the active ingredient may be combined with various sweetening orflavoring agents, coloring matter or dyes, and, if so desired,emulsifying and/or suspending agents as well, together with suchdiluents as water, ethanol, propylene glycol, glycerin and various likecombinations thereof.

For parenteral administration, solutions of a compound of the presentinvention in either sesame or peanut oil or in aqueous propylene glycolmay be employed. The aqueous solutions should be suitably buffered(preferably pH greater than 8) if necessary and the liquid diluent firstrendered isotonic. These aqueous solutions are suitable for intravenousinjection purposes. The oily solutions are suitable for intra-articular,intra-muscular and subcutaneous injection purposes. The preparation ofall these solutions under sterile conditions is readily accomplished bystandard pharmaceutical techniques well known to those skilled in theart.

For intranasal administration or administration by inhalation, the novelcompounds of the invention are conveniently delivered in the form of asolution or suspension from a pump spray container that is squeezed orpumped by the patient or as an aerosol spray presentation from apressurized container or a nebulizer, with the use of a suitablepropellant, e.g., dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol, the dosage unit may be determined byproviding a valve to deliver a metered amount. The pressurized containeror nebulizer may contain a solution or suspension of the activecompound. Capsules and cartridges (made, for example, from gelatin) foruse in an inhaler or insufflator may be formulated containing a powdermix of a compound of the invention and a suitable powder base such aslactose or starch. Formulations of the active compounds of thisinvention for treatment of the conditions referred to above in theaverage adult human are preferably arranged so that each metered dose or“puff” of aerosol contains 20 μg to 1000 μg of active compound. Theoverall daily dose with an aerosol will be within the range 100 μg to 10mg. Administration may be several times daily, for example 2, 3, 4 or 8times, giving for example, 1, 2 or 3 doses each time.

The compounds of the present invention can be prepared and administeredin a wide variety of oral and parenteral dosage forms. Thus, thecompounds of the present invention can be administered by injection,that is, intravenously, intramuscularly, intracutaneously,subcutaneously, intraduodenally, or intraperitoneally. Also, thecompounds of the present invention can be administered by inhalation,for example, intranasally. Additionally, the compounds of the presentinvention can be administered transdermally. It will be obvious to thoseskilled in the art that the following dosage forms may comprise as theactive component, either a compound of formula 1, IA, IA-1, IA-2, IB,IC, II, IIA, III, or IV or a corresponding pharmaceutically acceptablesalt of such compound.

For preparing pharmaceutical compositions from the compounds of thepresent invention, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,pills, capsules, cachets, suppositories, and dispersible granules. Asolid carrier can be one or more substances which may also act asdiluents, flavoring agents, binders, preservatives, tabletdisintegrating agents, or an encapsulating material. In powders, thecarrier is a finely divided solid which is in a mixture with the finelydivided active component. In tablets, the active component is mixed withthe carrier having the necessary binding properties in suitableproportions and compacted in the shape and size desired.

The powders and tablets preferably contain from five or ten to aboutseventy percent of the active compound. Suitable carriers are magnesiumcarbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin,starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as a carrier providing acapsule in which the active component with or without other carriers, issurrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid dosage formssuitable for oral administration.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogenous mixture is then poured into convenient sized molds, allowedto cool, and thereby to solidify.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water propylene glycol solutions. For parenteralinjection liquid preparations can be formulated in solution in aqueouspolyethylene glycol solution. Aqueous solutions suitable for oral usecan be prepared by dissolving the active component in water and addingsuitable colorants, flavors, stabilizing and thickening agents asdesired. Aqueous suspensions suitable for oral use can be made bydispersing the finely divided active component in water with viscousmaterial, such as natural or synthetic gums, resins, methylcellulose,sodium carboxymethylcellulose, and other well-known suspending agents.

Also included are solid form preparations that are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

The pharmaceutical preparation is preferably in unit dosage form. Insuch form the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsules, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

The quantity of active component in a unit dose preparation may bevaried or adjusted from 0.01 mg to 1 g according to the particularapplication and the potency of the active component. In medical use thedrug may be administered three times daily as, for example, capsules of100 or 300 mg. The composition can, if desired, also contain othercompatible therapeutic agents.

In therapeutic use, the compounds utilized in the pharmaceutical methodof this invention are administered at the initial dosage of about 0.1 mgto about 1 g daily. The dosages, however, may be varied depending uponthe requirements of the patient, the severity of the condition beingtreated, and the compound being employed. Determination of the properdosage for a particular situation is within the skill of the art.Generally, treatment is initiated with smaller dosages which are lessthan the optimum dose of the compound. Thereafter, the dosage isincreased by small increments until the optimum effect under thecircumstances is reached. For convenience, the total daily dosage may bedivided and administered in portions during the day, if desired.

The following Examples illustrate the preparation of the compounds ofthe present invention. They are not meant to be limiting in scope.Melting points are uncorrected. NMR data are reported in parts permillion and are referenced to the deuterium lock signal from the samplesolvent.

EXAMPLES Example 1 (3S,5R)-3-Amino-5-methyl-octanoic acid hydrochloride

(R)-2,6-Dimethyl-non-2-ene. To (S)-citronellyl bromide (50 g, 0.228 mol)in THF (800 mL) at 0° C. was added LiCl (4.3 g) followed by CuCl₂ (6.8g). After 30 minutes methylmagnesium chloride (152 mL of a 3 M solutionin THF, Aldrich) was added and the solution warmed to room temperature.After 10 hours the solution was cooled to 0° C. and a saturated aqueoussolution of ammonium chloride carefully added. The resultant two layerswere separated and the aqueous phase extracted with ether. The combinedorganic phases were dried (MgSO₄) and concentrated to give(R)-2,6-dimethyl-non-2-ene. 32.6 g; 93%. Used without furtherpurification. ¹H NMR (400 MHz; CDCl₃) δ 5.1 (m, 1H), 1.95 (m, 2H), 1.62(s, 3H), 1.6 (s, 3H), 1.3 (m, 4H), 1.2 (m, 2H), 0.8 (s, 6H);¹³C NMR (100MHz; CDCl₃) δ 131.13, 125.28, 39.50, 37.35, 32.35, 25.92, 25.77, 20.31,19.74, 17.81, 14.60.

(R)-4-Methyl-heptanoic acid. To (R)-2,6-dimethyl-non-2-ene (20 g, 0.13mol) in acetone (433 mL) was added a solution of CrO₃ (39 g, 0.39 mol)in H₂SO₄ (33 mL)/H₂O (146 mL) over 50 minutes. After 6 hours a furtheramount of CrO₃ (26 g, 0.26 mol) in H₂SO₄ (22 mL)/H₂O (100 mL) was added.After 12 hours the solution was diluted with brine and the solutionextracted with ether. The combined organic phases were dried (MgSO₄) andconcentrated. Flash chromatography (gradient of 6:1 to 2:1 hexane/EtOAc)gave (R)-4-methyl-heptanoic acid as an oil. 12.1 g; 65%. MS, m/z(relative intensity): 143 [M-H, 100%]; ¹H NMR (400 MHz; CDCl₃) δ 2.35(m, 2H), 1.6 (m, 1H), 1.4 (m, 1H), 1.3 (m, 4H), 1.1 (m, 1H), 0.85 (s,6H).

(4R,5S)-4-Methyl-3-((R)-4-methyl-heptanoyl)-5-phenyl-oxazol idin-2-one.To (R)-4-methyl-heptanoic acid (19 g, 0.132 mol) and triethylamine (49.9g, 0.494 mol) in THF (500 mL) at 0° C. was added trimethylacetylchloride(20 g, 0.17 mol). After 1 hour LiCl (7.1 g, 0.17 mol) was added followedby (4R,5S)-(+)-4-methyl-5-phenyl-2-oxazolidinone) 3 (30 g, 0.17 mol).The mixture was warmed to room temperature and after 16 hours thefiltrate was removed by filtration and the solution concentrated underreduced pressure. Flash chromatography (7:1 hexane/EtOAc) gave(4R,5S)-4-methyl-3-((R)-4-methyl-heptanoyl)-5-phenyl-oxazolidin-2-one asan oil. 31.5 g; 79%. [α]D=+5.5 (c 1 in CHCl₃). MS, m/z (relativeintensity): 304 [M+H, 100%]; ¹H NMR (400 MHz; CDCl₃) 87.4-7.2 (m, 5H),5.6 (d, J=7.32 Hz, 1H), 4.75 (m, 1H), 2.96 (m, 1H), 2.86 (m, 1H), 1.62(m, 1H), 1.43 (m, 1H), 1.25 (m, 4H), 1.12 (m, 1H), 0.85 (m, 9H); ¹³C NMR(100 MHz; CDCl₃) δ 173.70, 153.23, 133.81, 133.59, 128.92, 128.88,128.92, 128.88, 125.83, 79.12, 54.93, 39.24, 33.66, 32.32, 31.47, 27.18,26.52, 20.25, 19.57, 14.75, 14.52.

(3S,5R)-5-Methyl-3-((4R,5S)-4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbonyl)-octanoicacid tert-butyl ester. To(4R,5S)-4-methyl-3-((R)-4-methyl-heptanoyl)-5-phenyl-oxazolidin-2-one(12.1 g, 0.04 mol) in THF (200 ml) at −50° C. was added sodiumbis(trimethylsilyl)amide (48 mL of a 1 M solution in THF). After 30 mint-butylbromoaceate (15.6 g, 0.08 mol) was added. The solution wasstirred for 4 hours at −50° C. and then warmed to room temperature.After 16 hours a saturated aqueous solution of ammonium chloride wasadded and the two layers separated. The aqueous phase was extracted withether and the combined organic phases dried (MgSO₄) and concentrated.Flash chromatography (9:1 hexane/EtOAc) gave(3S,5R)-5-methyl-3-((4R,5S)-4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbonyl)-octanoicacid tert-butyl ester as a white solid 12 g; 72%. [α]D=+30.2 (c 1 inCHCl₃).¹³C NMR (100 MHz; CDCl₃) δ 176.47, 171.24, 152.72, 133.63,128.87, 125.86, 80.85, 78.88, 55.34, 39.98, 38.77, 38.15, 37.58, 30.60,28.23, 20.38, 20.13, 14.50, 14.28.

(S)-2-((R)-2-Methyl-pentyl)-succinic acid 4-tert-butyl ester. To(3S,5R)-5-methyl-3-((4R,5S)-4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbonyl)-octanoicacid tert-butyl ester (10.8 g, 0.025 mol) in H₂O (73 mL) and THF (244mL) at 0° C. was added a premixed solution of LiOH (51.2 mL of a 0.8 Msolution) and H₂O₂ (14.6 mL of a 30% solution). After 4 hours a further12.8 mL LiOH (0.8 M solution) and 3.65 mL of H₂O₂ (30% solution) wasadded. After 30 minutes sodium bisulfite (7 g), sodium sulfite (13 g),and water (60 mL) was added followed by hexane (100 mL) and ether (100mL). The two layers were separated and the aqueous layer extracted withether. The combined organic phases were concentrated to an oil that wasdissolved in heptane (300 mL). The resultant solid was filtered off andthe filtrate dried (MgSO₄) and concentrated to afford(S)-2-((R)-2-methyl-pentyl)-succinic acid 4-tert-butyl ester (6 g, 93%)which was used immediately without further purification. MS, m/z(relative intensity): 257 [M+H, 100%].

(3S, 5R)-3-Benzyoxycarbonylamino-5-methyl-octanoic acid, tert-butylester. A solution of (S)-2-((R)-2-methyl-pentyl)-succinic acid4-tert-butyl ester (6.0 g, 23.22 mmol) and triethylamine (3.64 mL, 26.19mmol) in toluene (200 mL) was treated with diphenylphosphoryl azide (5.0mL, 23.22 mL) and stirred at room temperature for 0.5 hours. After thereaction mixture was then heated at reflux for 3 h and cooled briefly,benzyl alcohol was added (7.2 mL, 69.7 mmol) and the solution heated foranother 3 h. After the reaction mixture was allowed to cool, it wasdiluted with ethyl ether (200 mL) and the combined organic layer waswashed successively with saturated NaHCO₃ and brine and dried (Na₂SO₄).The concentrated organic component was purified by chromatography (MPLC)eluting with 8:1 hexanes: ethyl acetate to provide (3S,5R)-3-benzyoxycarbonylamino-5-methyl-octanoic acid, tert-butyl ester(6.4 g, 75.8%). MS: M+1: 364.2, 308.2. ¹HNMR (400 MHz, CDCl₃) δ 0.83 (t,3H, J=6.59 Hz), 0.87 (d, 3H, J=6.59 Hz), 1.08-1.34 (m, 6H), 1.39 (s,9H), 1.41-1.52 (m, 2H), 2.39 (m, 2H), 4.02 (m, 1H), 5.05 (s, 2H), 5.09(m, 1H), and 7.24-7.32 (m, 5H) ppm.

(3S, 5R)-3-Amino-5-methyl-octanoic acid, tert-butyl ester. A solution of(3S, 5R)-3benzyoxycarbonylamino-5-methyl-octanoic acid, tert-butyl ester(2.14 g, 5.88 mmol) in THF (50 mL) was treated with Pd/C (0.2 g) and H₂at 50 psi for 2 hours. The reaction mixture was then filtered andconcentrated to an oil in vacuo to give (3S,5R)-3-amino-5-methyl-octanoic acid, tert-butyl ester in quantitativeyield. MS: M+1: 230.2, 174.1. ¹HNMR (400 MHz, CDCl₃) δ 0.85-0.86(overlapping t and d, 6H), 1.13-1.40 (m, 6H), 1.44 (s, 9H), 1.60 (m,1H), 2.31 (dd, 1H, J=7.81 and 15.86 Hz), 2.38(dd, 1H, J=5.13 and 15.86Hz), 3.31 (m,1H), and 3.45(br s, 2H) ppm. (3S,5R)-3-Amino-5-methyl-octanoic acid hydrochloride. A slurry of (3S,5R)-amino-5-methyl-octanoic acid, tert-butyl ester (2.59 g, 11.3 mmol)in 6N HCl (100 mL) was heated under reflux 18 hours, cooled, andfiltered over Celite. The filtrate was concentrated in vacuo to 25 mLand the resulting crystals were collected and dried to provide (3S,5R)-3-amino-5-methyl-octanoic acid hydrochloride, mp 142.5-142.7° C.(1.2 g, 50.56%). A second crop (0.91 g) was obtained from the filtrate.Anal. Calc'd for CgH₁₉NO₂-HCl: C: 51.55, H: 9.61, N: 6.68, Cl: 16.91.Found: C: 51.69, H: 9.72, N: 6.56, Cl: 16.63. MS: M+1: 174.1. ¹HNMR(CD3OD) δ 0.89 (t, 3H, J=7.32 Hz), 0.92 (d, 3H, J=6.35 Hz), 1.12-1.18(m, 1H), 1.25-1.35 (m, 2H), 1.35-1.42 (m, 2H), 1.54-1.64 (m, 2H), 2.50(dd, 1H, J=7.81 and 17.33 Hz), 2.65 (dd, 1H, J=4.64 and 17.32 Hz), and3.52 (m, 1H) ppm.

(3S, 5R)-3-Amino-5-methyl-octanoic acid hydrochloride acid salt. 5.3 gof 2S-(2R-methyl-pentyl)-succinic acid-4-tert-butyl ester contained in30 mL methyltertbutyl ether is reacted at room temperature with 3.5 mLtriethylamine followed by 6.4 g of diphenylphosphoryl azide. Afterallowing the reaction to exotherm to 45° C. and stirring for at least 4hours, the reaction mixture is allowed to cool to room temperature andstand while the phases separated. The lower layer is discarded and theupper layer is washed with water, followed by dilute aqueous HCl. Theupper layer is then combined with 10 mL of 6 N aqueous HCl, and stirredat 45-65° C. The reaction mixture is concentrated by vacuum distillationto about 10-14 mL and allowed to crystallize while cooling to about 5°C. After collecting the product by filtration, the product is washedwith toluene and reslurried in toluene. The product is dried by heatingunder vacuum resulting in 2.9 g (67%) of white crystalline product. Theproduct may be recrystallized from aqueous HCl. mp 137° C., HNMR (400MHz, D6 DMSO) delta 0.84-0.88 (overlapping d and t, 6H), 1.03-1.13 (m,1H), 1.16- 1.37 (m,4H), 1.57-1.68 (m, 2H), 2.55 (dd, 1H, J=7, 17 Hz),2.67 (dd, 1H, J=6, 17 Hz), 3.40 (m, 1H), 8.1 ( br s, 3H), 12.8 (br s,1H).

Example 2. (3S, 5R)-Amino-5-methyl-hoeptanoic Acid

Methanesulfonic acid (S)-3,7-dimethyl-oct-6enyl ester. ToS-(−)-citronellol (42.8 g, 0.274 mol) and triethylamine (91 mL, 0.657mol) in CH₂Cl₂ (800 mL) at 0° C. was added methanesulphonyl chloride (26mL, 0.329 mol) in CH₂Cl₂ (200 mL). After 2 hours at 0° C. the solutionwas washed with 1 N HCl then brine. The organic phase was dried (MgSO₄)and concentrated to afford the titled compound an oil (60.5 g, 94%)which was used without further purification. MS, m/z (relativeintensity): 139 [100%],143 [100%]. ¹H NMR (400 MHz; CDCl₃) δ 5.05 (1H,m),4.2 (2H, m), 2.95 (3H, s), 1.98 (2H, m), 1.75 (1H, m), 1.6 (3H,s),1.5 (4H, m), 1.35 (2H, m), 1.2 (1 H, m), 0.91 (3H, d, J=6.5 Hz).

(R)-2,6-Dimethyl-oct-2ene. To methanesulfonic acid(S)-3,7-dimethyl-oct-6-enyl ester (60 g, 0.256 mol) in THF (1 L) at 0°C. was added lithium aluminum hydride (3.8 g, 0.128 mol). After 7 hours,a further 3.8 g of lithium aluminum hydride was added and the solutionwarmed to room temperature. After 18 hours, a further 3.8 g of lithiumaluminum hydride was added. After a further 21 hours, the reaction wascarefully quenched with 1N citric acid and the solution diluted furtherwith brine. The resultant two phases were separated and the organicphase was dried (MgSO₄) and concentrated to afford the titled compoundas an oil which was used without further purification. MS, m/z (relativeintensity): 139 [M+H, 100%].

(R)-4-Methyl-hexanoic acid. A procedure similar to the synthesis of(R)-4-methyl-heptanoic acid was utilized giving the acid as an oil (9.3g, 56%). 1R (film) 2963, 2931, 2877, 2675, 1107, 1461, 1414 cm⁻¹; MS,m/z (relative intensity): 129 [M-H, 100%]; ¹H NMR (400 MHz; CDCl₃) 82.35(m, 2H), 1.66 (m, 1H), 1.37 (m, 4H), 1.29 (m, 1H), 0.86 (m, 6H); ¹³C NMR(100 MHz; CDCl₃) δ 181.02, 34.09, 32.12, 31.39, 29.29, 18.94, 11.44.

(4R,5S)4-Methyl-3-((R)4methyl-hexanoyl)-5-phenyl-oxazoldin-2-one. Aprocedure similar to the synthesis of(4R,5S)-4-methyl-3-((R)-4-methyl-heptanoyl)-5-phenyl-oxazolidin-2-onewas utilized giving the titled compound as an oil (35.7 g, 95%). MS, m/z(relative intensity): 290 [M+H, 100%]; ¹ H NMR (400 MHz; CDCl₃) δ7.4-7.25 (m, 5H), 5.6 (d, J=7.32 Hz, 1H), 4.75 (m, 1H), 2.97 (m,1H),2.85 (m,1H), 1.68 (m, 1H), 1.43 (m, 2H), 1.12 (m, 2H), 0.87 (m, 9H); ¹³CNMR (100 MHz; CDCl₃) δ 173.71, 153.24, 133.56, 128.94, 128.90, 125.83,79.14, 54.95, 34.22, 33.72, 31.07, 29.45, 27.20, 26.52, 19.19, 19.15,14.77, 14.53, 11.54.

(3S,5R)-5-Methyl-3-[1-((4R,5S)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-yl)-methanoyl]heptanoicacid tert-butyl ester. A procedure similar to the preparation of(3S,5R)-5-methyl-3-((4R,5S)-4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbonyl)-octanoicacid tert-butyl ester was followed giving the titled compound as an oil(7.48 g; 31%). IR (film) 2967, 2934, 1770, 1716, 1696, 1344, 1148, 1121,1068, 1037, 947 cm⁻¹; MS, m/z (relative intensity): 178 [100%], 169[100%]; [α]D=+21.6 (c 1 in CHCl₃).

(S)-2-((R)-2-Methyl-butyl)-succinic acid 4-tert-butyl ester.(3S,5R)-5-Methyl-3-[1-((4R,5S)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-yl)-methanoyl]-heptanoicacid tert-butyl ester (7.26 g, 0.018 mol) in H₂O (53 mL) and THF (176mL) at 0° C. was added a premixed solution of LiOH (37 mL of a 0.8 Msolution) and H₂O₂ (10.57 mL of a 30% solution) and the solution warmedto room temperature. After 2 hours sodium bisulfite (7 g), sodiumsulfite (13 g), and water (60 mL) was added and the two layers wereseparated and the aqueous layer extracted with ether. The combinedorganic phases were concentrated to an oil that was dissolved in heptane(200 mL). The resultant solid was filtered off and the filtrate dried(MgSO₄) and concentrated to afford the titled compound as an oil (4.4 g)that was used without further purification. MS, m/z (relativeintensity): 243 [100%]; ¹H NMR (400 MHz; CDCl₃) δ 2.88 (m, 1H), 2.59 (m,1H), 2.36 (m, 1H), 1.65 (m, 1H), 1.41 (s, 9H), 1.20 (m, 4H), 0.84 (m,6H)

(3S, 5R)-3-Benzyoxycarbonylamino-5-methyl-heptanoic acid, tert-butylester. This compound was prepared as described above starting with(S)-2-((R)-2-methyl-butyl) succinic acid, 4-tert-butyl ester to give(3S, 5R)-3-benzyoxycarbonylamino-5-methyl-heptanoic acid, tert-butylester as an oil (73.3% yield). ¹H NMR (400 MHz; CDCl₃) δ 0.84(t, 3H,J=7.33 Hz), 0.89(d, 3H, J=6.60 Hz), 1.12-1.38 (m, 4H), 1.41 (s, 9H),1.43-1.59 (m, 2H), 2.42 (m, 2H), 4.05 (m, 1H), 5.07 (t, 2H J=12.95 Hz),and 7.28-7.34 (m, 5H).

(3S, 5R)-Amino-5-methyl-heptanoic acid, tert-butyl ester. This compoundwas prepared as described above starting with (3S,5R)-3-benzyoxycarbonylamino-5-methyl-heptanoic acid, tert-butyl esterinstead of (3S, 5R)-3-benzyoxycarbonylamino-5-methyl-octanoic acid,tert-butyl ester to give the titled compound. ¹H NMR (400 MHz; CDCl₃) δ0.84 (overlapping t and d, 6H), 1.08-1.16(m, 2H), 1.27-1.30(m, 2H),1.42(s, 9H), 1.62 (br s, 2H), 2.15 (dd, 1H, J=8.54 and 15.62 Hz),2.29(dd, 1H, J=4.15 and 15.37 Hz), and 3.20(br s, 2H).

(3S, 5R)-Amino-5-methyl-heptanoic acid hydrochloride-A slurry of (3S,5R)-amino-5-methyl-heptanoic acid, tert-butyl ester (1.44 g, 6.69 mmol)in 3N HCl was heated at reflux for 3 hours, filtered hot over Celite,and concentrated to dryness. Trituration of the resulting solid in ethylether provided (3S, 5R)-3-amino-5-methyl-heptanoic acid hydrochloride,(0.95 g, 85%) mp 126.3-128.3° C. ¹H NMR (400 MHz; CD₃0D) δ 0.92 (t, 3H,J=7.32 Hz), 0.92 (d, 3H, J=6.35 Hz), 1.15-1.24 (m, 1H), 1.33-1.43 (m,2H), 1.44-1.52 (m, 1H), 1.60-1.67 (m, 1H), 2.57 (ddd, 1H, J=7.32 17.67and 5.12 Hz), 2.69 (ddd, 1H, J=0.97, 4.88 and 17.32 Hz), and 3.28 (m,1H). Anal. Calc'd for C₆H₁₇NO₂-HCl-0.1H₂O: C: 48.65, H: 9.29, N: 7.09,Cl: 17.95. Found: C: 48.61, H: 9.10, N: 7.27, Cl: 17.87MS: M+1: 160.2

Example 3 (3S, 5R)-3-Amino-5-methyl-nonanoic Acid

(R)-4-Methyl-octanoic acid. Lithium chloride (0.39 g, 9.12 mmol) andcopper (I) chloride (0.61 g, 4.56 mmol) were combined in 45 ml THF atambient temperature and stirred 15 minutes, then cooled to 0° C. atwhich time ethylmagnesium bromide (1 M solution in THF, 45 mL, 45 mmol)was added. (S)-citronellyl bromide (5.0 g, 22.8 mmol) was added dropwiseand the solution was allowed to warm slowly to ambient temperature withstirring overnight. The reaction was quenched by cautious addition ofsat. NH₄Cl (aq), and stirred with Et₂O and sat. NH₄Cl (aq) for 30minutes. The phases were separated and the organic phase dried (MgSO₄)and concentrated. The crude (R)-2,6-dimethyl-dec-2-ene was used withoutpurification. To a solution of (R)-2,6-dimethyl-dec-2-ene (3.8 g, 22.8mmol) in 50 mL acetone at 0° C. was added Jones' reagent (2.7 M in H₂SO₄(aq), 40 mL, 108 mmol) and the solution was allowed to warm slowly toambient temperature with stirring overnight. The mixture was partitionedbetween Et₂O and H₂O, the phases were separated, and the organic phasewashed with brine, dried (MgSO₄), and concentrated. The residue waspurified by flash chromatography (8:1 hexanes:EtOAc) to afford 2.14 g(59%) of the titled compound as a colorless oil: LRMS: m/z 156.9 (M+);¹H NMR (400 MHz; CDCl₃): δ 2.33 (m, 2H), 1.66 (m, 1H), 1.43 (m, 2H),1.23 (m, 5H), 1.10 (m, 1H), 0.86 (m, 6H). Jones' reagent was prepared asa 2.7M solution by combining 26.79 CrO₃, 23 mL H₂SO₄, and diluting to100 mL with H₂O.

(4R, 5S)-4-Methyl-3-((R)-4-methyl-octanoyl)-5-phenyl-oxazolidin-2-one.To (R)-4-methyl-octanoic acid (2.14 g, 13.5 mmol) in 25 mL CH₂Cl₂ at 0°C. was added 3 drops DMF, followed by oxalyl chloride (1.42 mL, 16.2mmol) resulting in vigorous gas evolution. The solution was warmeddirectly to ambient temperature, stirred 30 minutes, and concentrated.Meanwhile, to a solution of the oxazolidinone (2.64 g, 14.9 mmol) in 40mL THF at −78° C. was added n-butyllithium (1.6 M soin in hexanes, 9.3mL, 14.9 mmol) dropwise. The mixture was stirred for 10 minutes at whichtime the acid chloride in 10 mL THF was added dropwise. The reaction wasstirred 30 minutes at −78° C., then warmed directly to ambienttemperature and quenched with sat. NH₄Cl. The mixture was partitionedbetween Et₂O and sat. NH₄Cl (aq), the phases were separated, and theorganic phase dried (MgSO₄), and concentrated to furnish 3.2 g of thetitled compound as a colorless oil. LRMS: m/z 318.2 (M+); ¹H NMR (400MHz; CDC;₃): δ 7.34 (m, 5H), 5.64 (d, J=7.3 Hz, 1H), 4.73 (quint, J=6.8Hz, 1H), 2.96 (m, 1H), 2.86 (m, 1H), 1.66 (m, 1H), 1.47 (m, 2H), 1.26(m, 5H), 1.13 (m, 1H), 0.88 (m, 9H). The crude product was used withoutpurification.

(3S,5R)-5-Methyl-3-((4R,5S)-4-methyl-2-oxo-5-phenyl-oxazoldine-3-carbonyl)-nonanoicacid tert-butyl ester. To a solution of diisopropylamine (1.8 mL, 12.6mmol) in 30 mL THF at −78° C. was added n-butyllithium (1.6 M soln inhexanes, 7.6 mL, 12.1 mmol), and the mixture stirred 10 minutes at whichtime (4R,5S)-4-Methyl-3-((R)4-methyl-octanoyl)-5-phenyl-oxazolidin-2-one (3.2 g,10.1 mmol) in 10 mL THF was added dropwise. The solution was stirred for30 minutes, t-butyl bromoacetate (1.8 mL, 12.1 mmol) was added quicklydropwise at −50° C., and the mixture was allowed to warm slowly to 10°C. over 3 hours. The mixture was partitioned between Et₂O and sat. NH₄Cl(aq), the phases were separated, and the organic phase dried (MgSO₄),and concentrated. The residue was purified by flash chromatography (16:1to 8:1 hexanes:EtOAc) to provide 2.659 (61%) of the titled compound as acolorless crystalline solid, mp=84-86° C. [α]D²³+17.1 (c=1.00, CHCl₃);¹H NMR (400 MHz; CDCl₃): δ 7.34 (m, 5H), 5.62 (d, J=7.3 Hz, 1H), 4.73(quint, J=6.8 Hz, 1H), 4.29 (m, 1H), 2.67 (dd, J=9.8, 16.4 Hz, 1H), 2.40(dd, J=5.1, 16.4 Hz, 1H), 1.69 (m, 1H), 1.38 (s, 9H), 1.28 (m, 7H), 1.08(m, 1H), 0.88 (m, 9H); ¹³C NMR (400 MHz; CDCl₃) δ 176.45, 171.22,152.71, 133.64, 128.86, 125.86, 80.83, 78.87, 55.33, 40.02, 38.21,37.59, 36.31, 30.86, 29.29, 28.22, 23.14, 20.41, 14.36, 14.26. Anal.Calcd for C₂₅H₃₇NO₅: C, 69.58; H, 8.64; N, 3.25. Found: C, 69.37; H,8.68; N, 3.05.

(S)-2-((R)-2-Methyl-hexyl)-succinic acid 4-tert-butyl ester. To asolution of(3S,5R)-5-Methyl-3-((4R,5S)-4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbonyl)-nonanoicacid tert-butyl ester (2.65 g, 6.14 mmol) in 20 mL THF at 0° C. wasadded a precooled (0° C.) solution of LiOH monohydrate (1.0 g, 23.8mmol) and hydrogen peroxide (30 wt % aqueous soln, 5.0 mL) in 10 mL H₂O.The mixture was stirred vigorously for 90 minutes, then warmed toambient temperature and stirred 90 minutes. The reaction was quenched at0° C. by addition of 100 mL 10% NaHSO₃ (aq), then extracted with Et₂O.The phases were separated, and the organic phase washed with brine,dried (MgSO₄), and concentrated. The titled compound was used withoutpurification.

(3S, 5R)-3-Benzyoxycarbonylamino-5-methylnonanoic acid, tert-butylester-This compound was prepared similarly as described above startingwith (S)-2-((R)-2-methylhexyl) succinic acid, 4-tert-butyl ester insteadof (S)-2-((R)-2-methylpentyl) succinic acid, 4-tert-butyl ester toprovide the titled compound as an oil (71.6% yield). ¹HNMR (400 MHz;CDCl₃) δ 0.81(t, 3H, J=4.40 Hz), 0.85(d, 3H, J=6.55 Hz), 1.06-1.20(m,7H), 1.36(s, 9H), 1.38-1.50(m, 2H), 2.36(m, 2H), 3.99(m, 1H), 5.02(m+s,3H), and 7.28-7.28(m, 5H).

(3S, 5R)-3-Amino-5-methyl-nonanoic acid, tert-butyl ester. This compoundwas prepared as described above starting with (3S,5R)-benzyoxycarbonylamino-5-methyl-nonanoic acid, tert-butyl esterinstead of (3S, 5R)-3-benzyoxycarbonylamino-5-methyl-octanoic acid,tert-butyl ester. Yield=97%. ¹HNMR (400 MHz; CDCl₃) δ 0.82(overlapping dand t, 6H), 1.02-1.08(m, 1H), 1.09-1.36(m, 6H), 1.39(s, 9H), 1.47(br s,1H), 1.80(s, 2H), 2.13(dd, 1H, J=8.54 and 15.61 Hz), and 2.27(dd, 1H,J=4.15 and 15.38 Hz). (3S, 5R)-3-Amino-5-methyl-nonanoic acidhydrochloride-A mixture of (3S, 5R)-3-amino-5-methyl-nonanoic acid,tert-butyl ester (1.50 g, 6.16 mmol) in 3N HCl (100 mL) was heated atreflux for 3 hours, filtered hot over Celite, and concentrated to 30 mLin vacuo. The resulting crystals were collected, washed with additional3N HCl, and dried to provide the title compound, mp 142.5-143.3° C.Additional crops were obtained from the filtrate to provide 1.03 g(70.4%). ¹HNMR (400 MHz; CD₃OD) δ=0.91 (t, 3H, J=6.84 Hz), 0.92(d, 3H,J=6.35 Hz), 1.16-1.26(m, 1H), 1.27-1.35(m, 4H), 1.38-1.45(m, 1H), 1.61(br s, 1H), 1.63-1.68(m, 1H), 2.58 (dd, 1H, J=7.32 and 17.34 Hz),2.69(dd, 1H, J=5.13 and 17.59 Hz), and 3.59(m, 1H). Anal. Calc'd forC₁₀H₂₁NO₂-HCl: C: 53.68, H: 9.91, N: 6.26, Cl: 15.85. Found: C: 53.89,H: 10.11, N: 6.13. MS: M+1: 188.1.

Example 4 (2R, 4R)-2-Aminomethyl methyl-heptanoic Acid

5R-Methyl-3R-(4S-methyl-2-oxo-5R-phenyloxazolidine-3-carbonyl)octanoicacid. A solution of(3R,5R)-5-Methyl-3-((4S,5R)-4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbonyl)-octanoicacid tert-butyl ester(3.9 g, 9.34 mmol) in dichloromethane (150 mL) wastreated with trifluoroacetic acid (7.21 mL, 93.4 mL) and stirred 18hours at ambient temperature. After the solvents and reagent wereremoved in vacuo, the resulting residue was tritrurated in 100 mLhexanes to provide 3.38 g of the title compound (100%) mp 142-143° C. MSM+1=362.1. ¹H NMR (400 MHz; CDCl₃) δ 0.85(2t, 6H, J=7.1 Hz), 0.93(d, 3H,J=6.1 Hz), 1.14(m, 1H), 1.2-1.49(m, 6H), 2.56(dd, 1H, J=4.15 and 17.57Hz), 2.81(dd, 1H, J=17.33 and 10.74 Hz), 4.28(m, 1H), 4.74(quint, 1H,J=6.84 Hz), 5.64(d, 1H, J=7.32 Hz), 7.29-7.43(m, 5H).

[4R-Methyl-2R-(4S-methyl-2-oxo-5R-phenyloxazoiidlne-3-carbonyl)heptyl]carbamicacid benzyl ester. A solution of5R-methyl-3R-(4S-methyl-2-oxo-5R-phenyloxazolidine-3-carbonyl)octanoicacid (1.98 g, 5.48 mmol) and triethylamine (0.92 mL, 6.57 mmol) wastreated with diphenylphosphorylazide (1.2 mL, 5.48 mmol), stirred 30 minat ambient temperature and then heated at reflux for 3 hours. Aftercooling briefly, the reaction mixture was treated with benzyl alcohol(2.8 mL, 27.4 mmol) and heated for an additional 3 h at reflux. Thereaction mixture was cooled, diluted with ethyl ether (150 mL), washedsuccessively with said NaHCO₃ and brine, dried (MgSO₄) and concentratedin vacuo to an oil. Chromatography (MPLC, elution with 4:1 hexanes:ethylacetate) provided the title compound (2.0 g, 78.3%) as an oil. MSM+1=467.1. ¹H NMR (400 MHz; CDCl₃) δ 0.86(2t, 6H, J=7.1 Hz), 0.93(d, 3H,J=5.9 Hz), 1.14(m, 1H), 1.09-1.36(m, 6H), 1.50(d, 1H, J=5.2 Hz), 3.49(t,1H, J=6.1 Hz), 4.10(m, 1H), 4.71(quint, 1H, J=6.61 Hz), 5.06(d, 2H,J=3.42 Hz), 5.20(t, 1H, J=5.61 Hz), 5.64(d, 1H, J=7.08 Hz), 7.29-7.43(m,10H).

2R-(Benzyloxycarbonylaminomethyl)-4R-methylheptanoic acid. A solution of4R-methyl-2R-(4S-methyl-2-oxo-5R-phenyloxazolidine-3-carbonyl)heptyl]carbamicacid benzyl ester (4.12 g, 8.83 mmol) in 3:1 THF:water (100 mL) wascooled to 0° C. and treated with a mixture of 0.8 N LiOH (17.5 mL, 14mmol) and 30% H₂O₂ (4.94 mL, 44 mmol). After the reaction mixture wasstirred in the cold 3 hours, it was quenched with a slurry of NaHSO₃(2.37 g) and Na₂SO₃ (4.53 g) in water (30 mL) and stirred 1 hour. Thereaction mixture was diluted with ethyl ether (200 mL), partitioned, andthe organic layer washed with brine and dried (MgSO₄). The concentratedorganic extract was chromatographed (MPLC) eluting with ethyl acetate togive 1.25 g of 2R-(benzyloxycarbonylaminomethyl)-4R-methylheptanoic acid(46%). MS M+1=308.1. ¹H NMR (400 MHz; CDCl₃) δ 0.83(t, 3H, J=6.84 Hz),0.87(t, 3H, J=6.35 Hz), 1.14(m, 1H), 1.06-1.54(m, 7H), 2.7(br s, 1H),3.30(m, 2H), 5.05(q, 2H, J=12.2 Hz), 5.14(t, 1H, J=5.61 Hz), 7.30(br s,5H).

(2R,4R)-2-Amino4-methyl-heptanoic acid hydrochloride. A mixture of2R-(benzyloxycarbonylaminomethyl)-4R-methyl-heptanoic acid (1.25 g, 4.07mmol) and Pd/C (20%, 0.11 g) in methanol (50 mL) was hydrogenated at 50psi for 18 hours. After the catalyst was removed by filtration, thesolvent was removed in vacuo and the resulting solid triturated in etherto provide (2S, 4R)-2-amino4-methyl-heptanoic acid hydrochloride (0.28g, 40%) mp 226.3-228.0° C. MS M+1=174.0. ¹H NMR (400 MHz; CD₃OD) δ0.89(t+d, 6H, J=6.35 Hz), 1.11 (m, 1H), 1.25-1.40(m, 4H), 1.47-1.62(m,2H), 2.48(br s, 1H), 2.93(m, 2H). Anal. Calc'd for C₉H₁₉NO₂0.1 H₂O C:61.75 H: 11.06 N: 8.00. Found C: 61.85 H: 10.83 N: 8.01.

Example 5. 2-Aminomethyl4,4-dimethyl-heptanoic Acid Hydrochloride.

2-Cyano4,4dimethyl-hepta-2,6-dienoic acid ethyl ester. A solution of2,2-dimethyl-pent-4-enal (5.0 g, 44 mmol), cyano-acetic acid ethyl ester(5.12 mL, 48 mmol), piperidine (1.3 mL, 14 mmol) and acetic acid (4.52mL, 80 mmol) in 170 mL of toluene was heated under reflux for 18 hoursin a flask equipped with a Dean-Stark separator. Several mL of water wascollected in the trap. The reaction was cooled and washed with 1N HCl,NaHCO₃ and brine, successively. The organic layers were dried overNa₂SO₄ and concentrated to an oil. This oil was chromatographed elutingwith 20% of EtOAc in hexane to give a combination of two lots total 8.3g (91%). ¹H NMR (400 MHz; CDCl₃) 1.28 (s, 6H), 1.32 (t, 3H, J=7 Hz),2.26 (d, 2H, J=7.6 Hz), 4.27 (q, 2H, J=7.2 Hz), 5.08 (d, ₁ H, J=12 Hz),5.10(d, 1H, J=4 Hz),5.72(m, 1H).

2-Aminomethyl-4,4dimethyl-heptanoic acid hydrochloride.2-Cyano-4,4-dimethyl-hepta-2,6-dienoic acid ethyl ester (5.88 g, 28mmol) was dissolved in the mixture of 91 mL of ethanol and 6 mL of HCland treated with 0.4 g of PtO₂. The reaction was carried out under 100psi of hydrogen pressure at room temperature for 15 hours. The catalystwas filtered and filtrate was concentrated to give 3.8 g of the desiredproduct 2-aminomethyl-4,4-dimethyl-heptanoic acid ethyl ester as an oil.MS (APCI): 216.2 (M+1)⁺. This oil was refluxed in 75 mL of 6N HCl for 18hours. While the reaction was cooled, a precipitate formed. The solidwas filtered, washed with additional HCl solution and triturated withether to give the clean title compound. MS (APCI): 188.1 (M+1)⁺. 186.1(M−1)⁺. ¹H NMR (400 MHz; CD₃OD): 0.91 (9H, m), 1.30 (5H, m), 1.81 (dd,1H, J=7.2 Hz, 14.4 Hz), 2.72 (1H, m), 3.04 (2H, m); Anal. Calc'd forC₁₀H₂₁NO₂HCl: C: 53.68, H: 9.91, N: 6.26, Cl: 15.85; Found: C: 53.83, H:10.15, N: 6.22, Cl: 15.40. MP: 229.5-231.0° C.

Example 6 (S)-3-Amino-5,5-dimethyl-octanoic Acid

3-4,4-Dimethyl-heptanoyl)-(R)-4-methyl-(S)-5-phenyl-oxazolidin-2-one: Asolution of 4,4-dimethyl-heptanoic acid (1.58 g, 10 mmol) andtriethylamine (4.6 mL) in 50 mL THF was cooled to 0° C. and treated with2,2-dimethyl-propionyl chloride (1.36 mL). After one hour,4R-methyl-5S-phenyl-oxazolidin-2-one (1.95 g, 11 mmol) and lithiumchloride (0.47 g, 11 mmol) was added and the mixture was stirred for 18hours. The precipitate was filtered and washed thoroughly withadditional THF. The filtrate was concentrated in vacuo to give an oilysolid. This solid was dissolved in 200 mL Et₂O, washed successively withsaturated NaHCO₃, 0.5N HCl and saturated NaCl, dried (MgSO₄) andconcentrated in vacuo to give the title compound as an oil (3.0 g, 95%).¹HNMR (400 MHz; CDCl₃): 0.73-0.84 (m, 12H), 1.10-1.22 (m, 4H), 1.46-1.54(m, 2H), 2.75-2.87 (m, 2H), 4.70 (m, 1H, J=7 Hz), 5.59 (d, 1H, J=7 Hz),7.22-7.37 (m, 5H).

5,5-Dimethyl-(S)-3-((R)-4-methyl-2-oxo-(S)-5-phenyl-oxazolidine-3-carbonyl)-octanoicacid tert-butyl ester: According to example 1, 5.07 g (16 mmol) of3-(4,4-dimethyl-heptanoyl)-4-methyl-5-phenyl-oxazolidin-2-one, 18 mL(1N, 18 mmol) of NaHMDS solution and 4.72 mL (32 mmol) of bromo-aceticacid tert-butyl ester gave 3.40 g (49.3%) of the title compound as acrystalline solid. ¹HNMR (400 MHz; CDCl₃): 0.85-0.89 (m, 12H), 1.18-1.32(m, 6H), 1.41 (s, 9H), 1.88 (dd, 1H, J=6 Hz, 8.4 Hz), 2.41 (dd, 1H, J=6Hz, 16 Hz), 2.62 (dd, 1H, J=8.4 Hz, 16 Hz), 4.30-4.40 (m, 1H), 4.72 (m,1H), 5.62 (d, 1H, J=7 Hz), 7.30-7.40 (m, 5H). m.p.: 83-85° C.

(S)2-(2,2-Dimethyl-pentyl)-succinic acid 4-tert-butyl ester: Accordingto example 1, 3.4 g (7.9 mmol) of5,5-dimethyl-3-(4-methyl-2oxo-5-phenyl-oxazolidine-3-carbonyl)-octanoicacid tert-butyl ester, 16 mL (12.8 mmol) of 0.8N LiOH and 4.5 mL of 30%H₂O₂ gave 2.42 g (>100%) of the title compound as an oil. ¹HNMR (400MHz; CDCl₃): 0.77-0.82 (m, 9H), 1.14-1.29 (m, 5H), 1.42 (s, 9H), 1.77(dd, 1H, J=8 Hz, 16 Hz), 2.36 (dd, 1H, J=6 Hz, 16 Hz), 2.59 (dd, 1H, J=8Hz, 16 Hz), 2.75-2.85 (m, 1H).

(S)-3-Benzyloxycarbonylamino-5,5-dimethyl-octanoic acid tert-butylester: According to example 1, 2.14 g (7.9 mmol)of2-(2,2-dimethyl-pentyl)-succinic acid 4-tert-butyl ester, 1.7 mL ofDPPA, 1.1 mL of Et₃N and 2.44 mL of BnOH provided 1.63 g (54.8% in twosteps) of the title compound as an oil. ¹HNMR (400 MHz; CDCl₃):0.78-0.89 (m, 9H), 1.10-1.30 (m, 5H), 1.36 (s, 9H), 2.39 (t, 2H, J=5Hz), 4.95-4.05 (m, 1H), 5.00 (s, 2H), 5.09 (d, 1H, J=9.6 Hz), 7.22-7.30(m, 5H).

(S)3-Amino-5,5-dimethyl-octanoic acid tert-butyl ester: According toexample 1, 1.63 g of 3-benzyloxycarbonylamino-5,5-dimethyl-octanoic acidtert-butyl ester and 0.2 g of 20% Pd/C furnished the title compound.¹HNMR (400 MHz; CDCl₃): 0.84-0.89 (m, 9H), 1.13-1.39 (m, 6H), 1.43 (s,9H), 2.25 (dd,1H, J=8.4 Hz, 15.6 Hz), 2.35 (dd,1H, J=4.4 Hz, 15.6 Hz),2.79 (s, br, 2H), 3.25-3.35 (m,1H). MS, m/z, 244.2 (M+1)⁺.

(S)-3-Amino-5,5-dimethyl-octanoic acid hydrochloride: According toexample 1, 3-amino-5,5-dimethyl-octanoic acid tert-butyl ester wastreated with 3N HCl to provide 286 mg of the title compound as a solid.¹HNMR (400 MHz; CD₃OD): 0.87-0.93 (m, 9H), 1.18-1.31(m, 4H), 1.51 (dd,1H, J=4 Hz, 14.4 Hz), 1.62 (dd, 1H, J=6.8 Hz, 14.4 Hz), 2.60 (dd, 1H,J=8 Hz, 17.6 Hz), 2.73 (dd, 1H, J=4 Hz, 7.6 Hz), 3.55-3.60 (m, 1H). MS(APCI), m/z 188.1 (M+1)⁺. 186.1 (M−1)⁺. Anal. Calc'd forC₁₀H₂₁NO₂.HCl.0.12H₂O: C: 53.17, H: 9.92, N: 6.20, Cl: 15.69; Found: C:53.19, H: 10.00, N: 6.08, Cl: 15.25. α=+20°(MeOH). MP: 194.2-195.2° C.

Example 7. 2-Aminomethyl-3-1-methyl-cyclopropyl)-propionic acid.

2-Cyano-3-(1-methyl-cyclopropyl)-acrylic acid ethyl ester. To1-methylcyclopropane-methanol (Aldrich, 1.13 mL, 11.6 mmol) in 50 mLCH₂Cl₂ was added neutral alumina (2.5 g) and then PCC (2.5 g, 11.6mmol), and the mixture stirred 3 h at ambient temperature. The mixturewas filtered through a 1 cm plug of silica gel under vacuum, and rinsedwith Et₂O. The filtrate was concentrated to ca. 5 mL total volume. Tothe residue was added THF (10 mL), ethyl cyanoacetate (1.2 mL, 11.3mmol), piperidine (5 drops), and finally acetic acid (5 drops). Thewhole was stirred at ambient temperature overnight, then partitionedbetween Et₂O and sat. aq. NaHCO₃. The phases were separated and theorganic phase washed with brine, dried (MgSO₄), and concentrated. Flashchromatography of the residue (10-15% EtOAc/hexanes) provided 0.53 g(25%) of the ester as a colorless oil that crystallized on standing, mp35-37° C. ¹H NMR (CDCl₃) δ 6.99 (s, 1H), 4.27 (q, J=7.3 Hz, 2H), 1.55(s, 3H), 1.32 (t, J=7.3 Hz, 3H), 1.14 (s, 2H), 1.07 (s, 2H). ¹³C NMR δ170.44, 162.90, 115.17, 103.69, 62.52, 21.24, 21.07 (2C), 20.71, 14.35.Anal. Calcd for C₁₀H₁₃NO₂: C, 67.02; H, 7.31; N, 7.82. Found: C, 66.86;H, 7.47; N, 7.70.

2-Aminomethyl-3-(1-methyl-cyclopropyl)-propionic acid ethyl ester. To2-cyano-3-(1-methyl-cyclopropyl)-acrylic acid ethyl ester (0.45 g, 2.51mmol) in 16 mL EtOH:THF (1:1) was added RaNi (0.4 g), and the mixturewas hydrogenated in a Parr shaker at 48 psi for 15.5 h. Pearlman'scatalyst (0.5 g) was then added and hydrogenation was continued for anadditional 15 h. The mixture was filtered and concentrated. Flashchromatography of the residue 2→3→→4→5→6→8% MeOH/CH₂Cl₂ provided 0.25 g(54%) of the aminoester as a colorless oil. ¹H NMR (CDCl₃) δ 3.97 (m,2H), 2.67 (m, 2H), 2.46 (m, 1H), 1.28 (d, J=7.3 Hz, 2H), 1.19 (bs, 2H),1.09 (t, J=7.3 Hz, 3H), 0.85 (s, 3H), 0.04 (m, 4H). LRMS: m/z 186.1(M+1).

2-Aminomethyl-3-(1-methyl-cyclopropyl)-propionic acid. To a solution of2-aminomethyl-3-(1-methyl-cyclopropyl)-propionic acid ethyl ester(0.259, 1.35 mmol) in 10 mL methanol at 0° C. was added 10% aq. NaOH (10mL). The mixture was stirred at ambient temperature overnight, thenconcentrated to remove the methanol. The residue was cooled to 0° C. andacidified to pH 2 with conc. HCl. After allowing to warm to ambienttemperature the mixture was loaded onto DOWEX-50WX8-100 ion exchangeresin and eluted with H₂O until neutral to litmus. Elution was continuedwith 5% aq. NH₄OH (100 mL) and the alkaline fractions concentrated toprovide 0.15 g (71%) of the amino acid as a colorless solid. ¹H NMR(CDCl₃) δ 2.72 (m, 2H), 2.42 (m, 1H), 1.34 (dd, J=8.5, 13.9 Hz, 1H),1.19 (dd, J=6.1, 13.9 Hz, 1H), 0.82 (s, 3H), 0.05 (m, 4H). LRMS: m/z158.0 (M+1).

Example 8 (3S,5R)-3-Amino-5-methyl-octanoic Acid

(5S)-5-Methyl-octa-2,6-dienoic acid tert-butyl ester. To a solution of(S)-3-methyl-hex-4-enoic acid ethyl ester* (1.0 g, 6.4 mmol) in 30 mLtoluene at −78° C. was added DIBAH (1.0 M in THF, 6.4 mL) dropwise over5 min. The mixture was stirred at −78° C. 45 min at which time 5 dropsof methanol were added, resulting in vigorous H₂ evolution. Methanol wasadded until no more gas evolution was observed (ca. 5 mL). At this timethe cold bath was removed and ca. 5 mL of sat. aq. Na⁺K⁺ tartrate wasadded. When the mixture reached room temperature, additional sat. aq.Na⁺K⁺ tartrate and Et₂O were added and stirring was continued until thephases were mostly clear (ca. 1 h). The phases were separated, and theorganic phase washed with brine, dried (MgSO₄), and concentrated to ca.10 mL total volume owing to volatility concerns. The crude mixture wascombined with an additional batch of aldehyde prepared from 10 mmol ofthe ester by the method described above and the whole used withoutpurification. To a suspension of sodium hydride (60% dispersion inmineral oil) in 25 mL THF was added t-butyl-P,P-dimethylphosphonoacetate(3.0 mL, 15 mmol) dropwise over 1 h such that the evolution of H₂ wasunder control. After the addition was complete, the crude aldehyde intoluene (ca. 20 mL total volume) was added quickly dropwise and themixture stirred at ambient temperature overnight. The mixture waspartitioned between Et₂O and sat. aq. NH₄Cl, the phases separated, theorganic phase washed with brine, dried (MgSO₄), and concentrated. Flashchromatography of the residue (0→3→5% EtOAc/hexanes) afforded 1.0 g(29%, two steps) of the unsaturated ester as a pale yellow oil: ¹H NMR(CDCl₃) δ 6.75 (m, 1H), 5.66 (m, 1H), 5.30 (m, 2H), 2.03-2.29 (m, 3H),1.58 (d, J=6.1 Hz, 3H), 1.41 (s, 9H), 0.91 (d, J=6.6 Hz, 3H).

*(S)-3-methyl-hex-4-enoic acid ethyl ester was prepared from(S)-trans-3-Penten-2-ol [Liang, J.; Hoard, D. W.; Van Khau, V.;Martinelli, M. J.; Moher, E. D.; Moore, R. E.; Tius, M. A. J. Org.Chem., 1999, 64, 1459] via Johnson-Claisen rearrangement withtriethylorthoacetate according to the literature protocol [Hill, R. K.;Soman, R.; Sawada, S., J. Org. Chem., 1972, 37, 3737].

(3R,5S)-3-[Benzyl-(1-phenyl-ethyl)-amino]-5-methyl-oct-6-enoic acidtert-butyl ester. To a solution of (S)-(−)-N-benzyl-α-methylbenzylamine(0.60 mL, 2.85 mmol) in 9.0 mL THF at −78° C. was added n-butyllithium(1.6 M in hexanes, 1.6 mL) quickly dropwise resulting in a deep pinkcolor. The mixture was stirred at −78° C. for 30 min at which time(5S)-5-Methyl-octa-2,6-dienoic acid tert-butyl ester (0.5 g, 2.38 mmol)in 1.0 mL THF was added slowly dropwise, resulting in a pale tan colorwhich darkened over 3 h. The mixture was stirred 3 h at −78° C., thenquenched with sat. aq. NH₄Cl. The mixture was allowed to warm to rt andstirred overnight, then partitioned between EtOAc and sat. aq. NH₄Cl.The phases were concentrated, and the organic phase dried (MgSO₄), andconcentrated. Flash chromatography of the residue (3→5% EtOAc/hexanes)provided 0.52 g (52%) of the aminoester as a yellow oil. ¹H NMR (CDCl₃)δ 7.34 (m, 2H), 7.20 (m, 8H), 5.27 (m, 2H), 3.74 (m, 1H), 3.72 (d,J=15.9 Hz, 1H), 3.41 (d, J=14.9 Hz, 1H), 3.27 (m, 1H), 2.38 (m, 1H),1.98 (dd, J=3.7, 14.2 Hz,1H), 1.81 (dd, J=9.3, 14.4 Hz,1H), 1.54 (d,J=4.9 Hz, 3H), 1.32 (s, 9H), 1.24 (d, J=7.1 Hz, 3H), 0.99 (m, 2H), 0.74(d, J=6.6 Hz, 3H).

(3S,5R)-3-Amino-5-methyl-octanoic acid. To a solution of(3R,5S)-3-[Benzyl-(1-phenyl-ethyl)-amino]-5-methyl-oct-6-enoic acidtert-butyl ester (0.92 g, 2.18 mmol) in 50 mL MeOH was added 20% Pd/C(0.20 g), and the mixture was hydrogenated in a Parr shaker at 48 psifor 23 h. The mixture was filtered and concentrated. To the crudeaminoester in 10 mL CH₂Cl₂ was added 1.0 mL trifluoroacetic acid, andthe solution stirred at ambient temperature overnight. The mixture wasconcentrated, and the residue dissolved in the minimum amount of H₂O,and loaded onto DOWEX-50WX8-100 ion exchange resin. The column waseluted with H₂O until neutral to litmus, then continued with 5% aq.NH₄OH (100 mL). The alkaline fractions were concentrated to provide 0.25g (66%, two steps) of the amino acid as an off-white solid. ¹H NMR(CD30D) δ 3.41 (m, 1H), 2.36 (dd, J=5.1, 16.6 Hz, 1H), 2.25 (dd, J=8.1,16.6 Hz, 1H), 1.42 (m, 2H), 1.24 (m, 1H), 1.12 (m, 2H), 1.00 (m, 1H),0.73 (d, J=6.4 Hz, 3H), 0.68 (t, J=6.8 Hz, 3H). LRMS: m/z 172.1 (M-1).

Example 9 2-Aminomethyl-8-methyl-nonanoic Acid

A procedure similar to that of 2-Aminomethyl-4,4,8-trimethyl-nonanoicacid was utilized to prepare 2-Aminomethyl-8-methyl-nonanoic acid from6-methyl-1-heptanol m/z202.1 (M+).

2-Aminomethyl-4,8-dimethyl-nonanoic Acid

(R)-2,6-dimethyl heptan-1-ol: Magnesium tumings (2.04 g, 84 mmol) and acrystal of iodine were suspended in 5 mL THF for the addition of1-bromo-3-methyl butane (0.3 mL, neat). The mixture was heated to startthe Grignard formation. The remaining 1-bromo-3-methyl butane (8.63 mL,72 mmol) was diluted in THF (60 mL) and added dropwise. The mixture wasstirred at ambient temperature for 2 hours and cooled to −5° C. Asolution of copper chloride (1.21 g, 9 mmol) and LiCl (0.76 g, 18 mmol)in THF (50 mL) was added dropwise keeping the temperature below 0° C.The resulting mixture was stirred for 20 min, and(R)-3-bromo-2-methylpropanol in THF (20 mL) was added dropwise whilekeeping the temperature below 0° C. The mixture was allowed to slowlyreach ambient temperature overnight. The reaction mixture was quenchedwith ammonium hydroxide and water. The mixture was diluted with EtOAcand extracted with 3×20 mL EtOAc. The organics were washed with brine,dried (MgSO₄), filtered and concentrated. The residual oil was purifiedvia silica gel chromatography (90/10 Hexane/EtOAc) to give 2.67 g(R)-2,6-dimethyl heptan-1-ol.

(R)-1-Iodo-2,6-dimethyl heptane: To a mixture of supported triphenylphosphine (6.55 g, 19.67 mmol) in CH₂Cl₂ at 0° C. was added iodine (4.99g, 19.67 mmol) and imidazole (1.33 g, 19.67 mmol). The mixture waswarmed to ambient temperature, stirred for 1 h and cooled to 0° C. forthe dropwise addition of (R)-2,6-dimethyl heptan-1-ol in CH₂Cl₂ (5 mL).The mixture was allowed to reach ambient temperature and stirred for 1h, at which time it was filtered through a pad of celite and the solidswere washed with CH₂Cl₂. The filtrated was concentrated, and the crudeproduct was purified via silica gel chromatography to give(R)-1-iodo-2,6-dimethyl heptane (2.44 g).

(4R)-4,8-dimethyl nonanoic acid t-butyl ester: To diisopropyl amine(0.827 mL, 5.9 mmol) in THF (8 mL) at -78° C. was added nBuLi (2.65 mLof a 2.6 M solution in pentane). The solution was stirred for 30 min at−78° C., followed by the addition of t-butyl acetate (0.8 mL, 5.9 mmol).The mixture was stirred at −78° C. for 2 h, and then(R)-1-iodo-2,6-dimethyl heptane (0.3 g, 1.18 mmol) and HMPA (1.5 mL) inTHF (1 mL) was added.

The reaction was stirred at −78° C. and allowed to slowly reach ambienttemperature overnight, then heated at 35° C. to drive the reaction tocompletion. The reaction was quenched by the addition of ammoniumchloride (saturated aqueous solution), and the mixture was extractedwith EtOAc (2×10 mL). The organics were combined, washed with water,dried (MgSO₄), filtered and concentrated. Silica gel chromatography(98/2 hexane/EtOAc) provided 0.25 g of (4R)-4,8-dimethyl nonanoic acidt-butyl ester.

(4R)-4,8-dimethyl nonanoic acid: (4R)-4,8-dimethyl nonanoic acid t-butylester in 25 mL CH₂Cl₂ at 0° C. was treated with TFA (6 mL). The mixturewas allowed to reach ambient temperature and stir overnight. The solventwas removed by rotary evaporation, and the mixture was purified bysilica gel chromatography (95/5 hexane/EtOAc) to give 0.962 g(4R)4,8-dimethyl nonanoic acid. m/z 185 (M−).

3-(4R,8-Dimethyl-nonanoyl)-4-(S)-methyl-5(R)-phenyl-oxazolidin-2-one: Aprocedure similar to(4R,5S)-4-Methyl-3-(R)-4-methyl-heptanoyl)-5-oxazolidin-2-one wasutilized to give3-(4R,8-Dimethyl-nonanoyl)-4(S)-methyl-5(R)-phenyl-oxazolidin-2-one(1.35 g) m/z 346.5 (M+).

[4R,8-Dimethyl-2R-(4R-methyl-2-oxo-5R-phenyl-oxazolidine-3-carbonyl)-nonyl]-carbamicacid benzyl ester: To a solution of3-4(R),8-Dimethyl-nonanoyl)-4(S)-methyl-5(R)-phenyl-oxazolidin-2-one(1.05 g, 3.04 mmol) in CH₂Cl₂ (12 mL) and TiCl₄ (3.04 mL of a 1 Msolution in CH₂Cl₂) was added diisopropyl ethyl amine (0.55 mL, 3.19mmol)at −20° C. The resulting dark red solution was stirred at −20° C.for 30 min prior to the addition of a solution of N-methoxymethyl benzylcarbamate (0.652 g, 3.34 mmol) in CH₂Cl₂ (3.5 mL) and TiCl₄ (3.34 mL).The mixture was stirred at 0° C. for 4 h. The reaction was quenched bythe addition of saturated aqueous ammonium chloride solution. Themixture was extracted with CH₂Cl₂ (3×15 mL). The organics were combinedand washed with 1 N HCl and neutralized with NaOH, followed by washingwith brine. The organics were dried (MgSO₄), filtered, concentrated andpurified by silica gel chromatography (95/5 hexane /EtOAc) to give 0.555g[4R,8-Dimethyl-2R-(4R-methyl-2-oxo-5R-phenyl-oxazolidine-3-carbonyl)-nonyl]-carbamicacid benzyl ester.

2(R)-(Benzyloxycarbonylamino-methyl)-4(R),8-dimethyl-nonanoic acid: Aprocedure similar to that of (S)-2-((R)-2-Methyl=pentyl)succinic acidt-butyl ester was utilized to provide 0.198 g2(R)-(Benzyloxycarbonylamino-methyl)-4-(R), 8-dimethyl-nonanoic acid.2-aminomethyl-4,8-dimethyl nonanoic acid:2(R)-(Benzyloxycarbonylamino-methyl)-4-(R), 8-dimethyl-nonanoic acid(0.148 g, 0.566 mmol) was treated with hydrogen in the presence of 20%pd/C to give 0.082 g of 2-aminomethyl-4,8-dimethyl nonanoic acid afterfiltration and purification via silica gel chromatography (85/15CH₂Cl₂/MeOH). m/z 216.3 (M+).

Example 10 2-Aminomethyl-4,4,8-trimethyl-nonanoic Acid

2,2,6-Trimethyl-heptanoic acid methyl ester: To diisopropyl amine (1.54mL, 11.03 mmol) in THF (22 mL) at −78° C. was added nBuLi (6.89 mL of a1.6 M solution in hexane). The solution was stirred for 30 min at −78°C., followed by the addition of methyl isobutyrate (0.97 mL, 8.48 mmol).The mixture was stirred at −78° C. for 2 h, and then 1-iodo-4-methylpentane (1.8 g, 8.48 mmol) and DMPU (0.55 mL, 4.24 mmol) in THF (6 mL)was added. The reaction was stirred at −78° C. and allowed to slowlyreach ambient temperature over 16 h. The reaction was quenched by theaddition of ammonium chloride (saturated aqueous solution), and themixture was extracted with EtOAc (2×10 mL). The organics were combined,washed with water, dried (MgSO₄), filtered and concentrated. Silica gelchromatography (99/1 hexane/EtOAc) provided 1.57 g of2,2,6-Trimethyl-heptanoic acid methyl ester.

2,2,6-Trimethyl-heptan-1-ol: 2,2,6-Trimethyl-heptanoic acid methyl ester(1.97 g, 10.6 mmol) was taken up in toluene (65 mL) and cooled to −78°C. DiBALH (12.7 mL of a 1 N solution in toluene) was added dropwise.After 45 min, 1.5 mL DiBALH was added. After 2 h, the reaction wasquenched by the addition of 15 mL MeOH at −78° C. The mixture was warmedto ambient temperature, and then cooled again to −78° C. for theaddition of 10 mL 1 N HCl. The mixture was extracted with EtOAc (3×15mL). The combined organics were washed with brine, dried (MgSO₄),filtered and concentrated. The residual oil was purified via silica gelchromatography (95/5 Hexane/EtOAc) to give 2,2,6-Trimethyl-heptan-1-ol(0.88 g). m/z 159 (M+).

2,2,6-Trimethyl-heptanal: Pyridinium chlorochromate (PCC, 4.17 g, 19.4mmol) was combined with neutral alumina (14.6 g) in CH₂Cl₂ and stirredat ambient temperature for 15 min. The alcohol was diluted in CH₂Cl₂,and the mixture was stirred at ambient temperature for 2 h. The solutionwas filtered through a pad of silica, and the solids were washed withCH₂Cl₂. The filtrate was evaporated to give 1.05 g m/z 157(M+).2,2,6-Trimethyl-heptanal which was carried on without furtherpurification.

2-Cyano-4,4,8-trimethyl-non-2-enoic acid benzyl ester: To a mixture of2,2,6-Trimethyl-heptanal (1.05 g, 6.73 mmol), piperidine (0.19 mL, 2.01mmol) and benzyl cyanoacetate (1.29 g, 7.4 mmol) in toluene (50 mL) wasadded glacial acetic acid (0.72 g, 12.1 mmol). The flask was fitted witha Dean-Stark trap, and the mixture was heated at reflux for 18. Themixture was cooled, treated with dilute HCl, and the layers wereseparated. The organics were washed with a saturated sodium bicarbonatesolution followed by brine, and dried (MgSO₄), filtered andconcentrated. The residual oil was purified by silica gel chromatography(98/2 hexane/EtOAc) to give 1.3 g of 2-Cyano-4,4,8-trimethyl-non-2-enoicacid benzyl ester m/z 314 (M+).

2-aminomethyl-4,4,8-trimethyl-nonanoic acid:2Cyano-4,4,8-trimethyl-non-2-enoic acid benzyl ester (1.3 g, 4.14 mmol)in THF (50 mL) was treated with hydrogen in the presence of 20% Pd/C togive a mixture of the cyano acid and the cyano methyl ester. The mixturewas purified by silica gel chromatography to give 278 mg of80105×41-1-2. The acid was then treated with hydrogen in the presence ofRaney Ni in MeOH/NH4OH to give 0.16 g of2-aminomethyl-4,4,8-trimethyl-nonanoic acid. m/z 230.3 (M+).

Example 11 2-Aminomethylethyl-octanoic Acid

A procedure similar to that of 2-Aminomethyl-4,4,8-trimethyl-nonanoicacid was utilized to prepare 2-Aminomethyl-4-ethyl-octanoic acid from2-ethylhexanal. m/z 202.1 (M+).

Example 12 2-Aminomethyl-4-ethyl-8-methyl-nonanoic Acid

A procedure similar to that of 2-Aminomethyl-4,4,8-trimethyl-nonanoicacid was utilized to prepare 2-Aminomethyl-8-methyl-nonanoic acid from2,6-di-t-butyl-4-methylphenyl cyclopropylcarboxylate. m/z 230.2 (M+).

Example 13 3-Amino-2-[1-(4-methyl-pentyl)-cyclopropylmethyl]-propionicAcid

A procedure similar to that of 2-Aminomethyl-4,4,8-trimethyl-nonanoicacid was utilized to prepare 2-Aminomethyl-8-methyl-nonanoic acid from2,6-di-t-butyl-4-methylphenyl cyclopropylcarboxylate. m/z 228.2 (M+).

Example 14 2-Aminomethyl-4-ethyl-hexanoic Acid

A procedure similar to 2-aminomethyl-4,8-dimethyl-nonanoic acid was usedto prepare 2-aminomethyl-4-ethyl-hexanoic acid from 4-ethyl hexanoicacid. m/z 174.1.

Example 15 3(S)Amino-3,5-dimethyl-heptanoic Acid

2-Methyl-propane-2(S)-sulfinic acid (1,3-dimethyl-pentylidene)-amide: Asolution of (S)-(−)-2-methyl-2-propanesulfonamide (500 mg, 4.1 mmol),4-methyl-2-hexanone (470 mg, 4.1 mmol), and Titanium(IV) ethoxide (1.7mL, 8.3 mmol) was heated at reflux for 18 h. The reaction mixture waspoured into 20 mL brine with rapid stirring. The resulting solution wasfiltered through celite, and the organic layer was separated. Theaqueous layer was extracted with ethyl acetate (2×20 mL). The combinedorganics were dried (Na₂SO₄), filtered, and concentrated. The resultantoil was purified by silica gel chromatography (25% EtOAc in hexane) togive 575 mg of 2-Methyl-propane-2(S)-sulfinic acid(1,3-dimethyl-pentylidene)-amide as a yellow oil.

3,5-Dimethyl-3-(2-methyl-propane-2(S)-sulfinylamino)-heptanoic acidmethyl ester: To a −78° C. solution of lithium bis(trimethylsilyl)amide(5.1 ml of a 1 M solution in THF) in THF (6 mL) was added methyl acetate((0.41 mL, 5.1 mmol) dropwise. After stirring for 20 min, a solution ofchlorotitanium triisopropoxide (2.5 ml, 10 mmol) in THF (3 mL) was addeddropwise. After 1 hour, 2-Methyl-propane-2(S)-sulfinic acid(1,3-dimethyl-pentylidene)-amide (560 mg, 2.6 mmol) in THF (3 mL) wasadded dropwise at −78° C. The reaction was stirred at −78° C. for 5 h,and then quenched by the addition of 10 mL ammonium chloride solutionand warmed to room temperature. The mixture was diluted with 10 mLwater, and filtered. The aqueous layer was extracted with ethyl acetate(2×20 mL). The combined organics were washed with brine, dried (Na2SO₄),filtered, and concentrated. The resultant oil was purified by silica gelchromatography (30% EtOAc in hexane) to give 360 mg of3,5-Dimethyl-3-(2-methyl-propane-2(S)-sulfinylamino)-heptanoic acidmethyl ester.

3(S)-Amino-3,5-dimethyl-heptanoicacid:3,5-Dimethyl-3-(2-methyl-propane-2(S)-sulfinylamino)-heptanoic acidmethyl ester (360 mg, 1.2 mmol) was dissolved in 6 N HCl (2 mL) anddioxane (2 mL) and heated at 100 C for 6 h. The mixture was cooled toroom temperature, diluted with water, and extracted with EtOAc (15 mL).The organics were purified by ion exchange chromatography to give3(S)-Amino-3,5-dimethyl-heptanoic acid (270 mg) and then repurificationby silica gel chromatography (70:25:5 CH₂Cl₂/MeOH/NH₄OH) to give 203 mgof 3(S)-Amino-3,5-dimethyl-heptanoic acid as a white solid. m/z 174(C₉H₁₉NO₂+H).

Example 16 3(S)Amino-3,5-dimethyl-nonanoic Acid

A procedure similar to that of 3(S)-Amino-3,5-dimethyl-heptanoic acidwas used to prepare 3(S)-Amino-3,5dimethyl-nonanoic acid. m/z 202.1(C₁₁H₂₃NO₂+H).

Example 17 3(S)-Amino-3,5-dimethyl-octanoic Acid

A procedure similar to that of 3(S)-Amino-3,5-dimethyl-heptanoic acidwas used to prepare 3(S)-Amino-3,5-dimethyl-nonanoic acid. m/z 188.1(C₁₀H₂₁NO₂+H).

1-2. (canceled)
 3. A compound of formula II,

or a pharmaceutically acceptable salt thereof; wherein R₁ is hydrogen or(C₁-C₃)alkyl optionally substituted with from one to five fluorineatoms; R₂ is hydrogen or (C₁-C₃)alkyl optionally substituted with fromone to five fluorine atoms; R₃ is (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl,(C₃-C₆)cycloalkyl-(C₁-c₃)alkyl, phenyl, phenyl-(C₁-C₃)alkyl, pyridyl,pyridyl-(C₁-C₃)alkyl, phenyl-N(H)—, or pyridyl-N(H)—, wherein each ofthe foregoing alkyl moieties is optionally substituted with from one tofive fluorine atoms, and wherein each of the foregoing phenyl andpyridyl moieties is optionally substituted with from one to threesubstituents independently selected from chloro, fluoro, amino, nitro,cyano, (C₁-C₃) alkylamino, (C₁-C₃)alkyl optionally substituted with fromone to three fluorine atoms, and (C₁-C₃)alkoxy optionally substitutedwith from one to three fluorine atoms; with the proviso that when R₁ ishydrogen, R₂ is not hydrogen.
 4. (canceled)
 5. A compound according toclaim 3, or a pharmaceutically acceptable salt thereof, the compoundrepresented by formula IIA,

wherein R₃ is (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl,(C₃-C₆)cycloalkyl-(C₁-C₃)alkyl, phenyl, phenyl-(C₁-C₃)alkyl, pyridyl,pyridyl-(C₁-C₃)alkyl, phenyl-N(H)—, or pyridyl-N(H)—, wherein each ofthe foregoing alkyl moieties can be is optionally substituted with fromone to five fluorine atoms, and wherein each of the foregoing phenyl andpyridyl moieties is optionally substituted with from one to threesubstituents independently selected from chloro, fluoro, amino, nitro,cyano, (C₁-C₃)alkylamino, (C₁-C₃)alkyl optionally substituted with fromone to three fluorine atoms, and (C₁-C₃)alkoxy optionally substitutedwith from one to three fluorine atoms.
 6. (canceled)
 7. A compound offormula III,

or a pharmaceutically acceptable salt thereof; wherein R₃ is(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl-(C₁-C₃)alkyl, phenyl,phenyl-(C₁-C₃)alkyl, pyridyl, pyridyl-(C₁-C₃)alkyl, phenyl-N(H)—, orpyridyl-N(H)—, wherein each of the foregoing alkyl moieties isoptionally substituted with from one to five fluorine atoms, and whereineach of the foregoing phenyl and pyridyl moieties is optionallysubstituted with from one to three substituents-, independently selectedfrom chloro, fluoro, amino, nitro, cyano, (C₁-C₃)alkylamino,(C₁-C₃)alkyl optionally substituted with from one to three fluorineatoms, and (C₁-C₃)alkoxy optionally substituted with from one to threefluorine atoms.
 8. A compound of formula IV,

or a pharmaceutically acceptable salt thereof; wherein R₁ is hydrogen or(C₁-C₆)alkyl optionally substituted with from one to five fluorineatoms; and R₃ is wherein R₃ is (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl,(C₃-C₆)cycloalkyl-(C₁-C₃)alkyl, phenyl, phenyl-(C₁-C₃)alkyl, pyridyl,pyridyl-(C₁-C₃)alkyl, phenyl-N(H)—, or pyridyl-N(H)—, wherein each ofthe foregoing alkyl moieties is optionally substituted with from one tofive fluorine atoms, and wherein each of the foregoing phenyl andpyridyl and the moieties is optionally substituted with from one tothree substituents, independently selected from chloro, fluoro, amino,nitro, cyano, (C₁-C₃)alkylamino, (C₁-C₃)alkyl optionally substitutedwith from one to three fluorine atoms, and (C₁-C₃)alkoxy optionallysubstituted with from one to three fluorine atoms. 9-14. (canceled) 15.A compound according to claim 3, or a pharmaceutically acceptable saltthereof, the compound selected from:2-aminomethyl-4-methyl-7-phenyl-heptanoic acid;2-aminomethyl-4-methyl-6-phenyl-hexanoic acid;2-aminomethyl-7-(4-fluoro-phenyl)-4-methyl-heptanoic acid;2-aminomethyl-7-(3-fluoro-phenyl)-4-methyl-heptanoic acid;2-aminomethyl-7-(2-fluoro-phenyl)-4-methyl-heptanoic acid;2-aminomethyl-7-(2,4-difluoro-phenyl)-4-methyl-heptanoic acid;2-aminomethyl-7-(3,4-difluoro-phenyl)-4-methyl-heptanoic acid;2-aminomethyl-4-methyl-7-(2-trifluoromethyl-phenyl)-heptanoic acid;2-aminomethyl-4-methyl-7-(3-trifluoromethyl-phenyl)-heptanoic acid;2-aminomethyl-4-methyl-7-(4-trifluoromethyl-phenyl)-heptanoic acid;2-aminomethyl-4-methyl-6-phenylamino-hexanoic acid;2-aminomethyl-4-methyl-7-phenylamino-heptanoic acid;2-aminomethyl-4-methyl-8-phenylamino-octanoic acid; (2R,4R)-2-aminomethyl-4-methyl-7-phenyl-heptanoic acid; (2R,4R)-2-aminomethyl-4-methyl-6-phenyl-hexanoic acid; (2R,4R)-2-aminomethyl-7-(4-fluoro-phenyl)-4-methyl-heptanoic acid; (2R,4R)-2-aminomethyl-7-(3-fluoro-phenyl)-4-methyl-heptanoic acid; (2R,4R)-2-aminomethyl-7-(2-fluoro-phenyl)-4-methyl-heptanoic acid; (2R,4R)-2-aminomethyl-7-(2,4-difluoro-phenyl)-4-methyl-heptanoic acid; (2R,4R)-2-aminomethyl-7-(3,4-difluoro-phenyl)-4-methyl-heptanoic acid; (2R,4R)-2-aminomethyl-4-methyl-7-(2-trifluoromethyl-phenyl)-heptanoic acid;(2R, 4R)-2-aminomethyl-4-methyl-7-(3-trifluoromethyl-phenyl)-heptanoicacid; (2R,4R)-2-aminomethyl-4-methyl-7-(4-trifluoromethyl-phenyl)-heptanoic acid;(2R, 4R)-2-aminomethyl-4-methyl-6-phenylamino-hexanoic acid; (2R,4R)-2-aminomethyl-4-methyl-7-phenylamino-heptanoic acid; (2R,4R)-2-aminomethyl-4-methyl-8-phenylamino-octanoic acid; (2R,4S)-2-aminomethyl-4-methyl-7-phenyl-heptanoic acid; (2R,4S)-2-aminomethyl-4-methyl-6-phenyl-hexanoic acid; (2R,4S)-2-aminomethyl-7-(4-fluoro-phenyl)-4-methyl-heptanoic acid; (2R,4S)-2-aminomethyl-7-(3-fluoro-phenyl)-4-methyl-heptanoic acid; (2R,4S)-2-aminomethyl-7-(2-fluoro-phenyl)-4-methyl-heptanoic acid; (2R,4S)-2-aminomethyl-7-(2,4-difluoro-phenyl)-4-methyl-heptanoic acid; (2R,4S)-2-aminomethyl-7-(3,4-difluoro-phenyl)-4-methyl-heptanoic acid; (2R,4S)-2-aminomethyl-4-methyl-7-(2-trifluoromethyl-phenyl)-heptanoic acid;(2R, 4S)-2-aminomethyl-4-methyl-7-(3-trifluoromethyl-phenyl)-heptanoicacid; (2R,4S)-2-aminomethyl-4-methyl-7-(4-trifluoromethyl-phenyl)-heptanoic acid;(2R, 4S)-2-aminomethyl-4-methyl-6-phenylamino-hexanoic acid; (2R,4S)-2-aminomethyl-4-methyl-7-phenylamino-heptanoic acid; (2R,4S)-2-aminomethyl-4-methyl-8-phenylamino-octanoic acid; (2R,4S)-2-aminomethyl-6-cyclohexyl-4-ethyl-hexanoic acid;2-aminomethyl-4-ethyl-hexanoic acid;2-aminomethyl-4-ethyl-5-methyl-hexanoic acid;2-aminomethyl-4-ethyl-heptanoic acid;2-aminomethyl-4-ethyl-6-methyl-heptanoic acid;2-aminomethyl-4-ethyl-octanoic acid;2-aminomethyl-4-ethyl-7-methyl-octanoic acid;2-aminomethyl-4-ethyl-nonanoic acid;2-aminomethyl-4-ethyl-8-methyl-nonanoic acid;2-aminomethyl-4,4-dimethyl-heptanoic acid;2-aminomethyl-4,6-dimethyl-heptanoic acid;2-aminomethyl-4,4,8-trimethyl-nonanoic acid (2R,4S)-2-aminomethyl-6-cyclopentyl-4-ethyl-hexanoic acid; (2R,4S)-2-aminomethyl-6-cyclobutyl-4-ethyl-hexanoic acid; (2R,4S)-2-aminomethyl-6-cyclopropyl-4-ethyl-hexanoic acid;2-aminomethyl-4-methyl-hexanoic acid; 2-aminomethyl-4-methyl-heptanoicacid; 2-aminomethyl-4-methyl-octanoic acid;2-aminomethyl-4-methyl-nonanoic acid; 2-aminomethyl-4-methyl-decanoicacid; (2R, 4R)-2-aminomethyl-4-methyl-hexanoic acid; (2R,4R)-2-aminomethyl-4-methyl-heptanoic acid; (2R,4R)-2-aminomethyl-4-methyl-octanoic acid; (2R,4R)-2-aminomethyl-4-methyl-nonanoic acid; (2R,4R)-2-aminomethyl-4-methyl-decanoic acid; (2R,4S)-2-aminomethyl-4-methyl-hexanoic acid; (2R,4S)-2-aminomethyl-4-methyl-heptanoic acid; (2R,4S)-2-aminomethyl-4-methyl-octanoic acid; (2R,4S)-2-aminomethyl-4-methyl-nonanoic acid; (2R,4S)-2-aminomethyl-4-methyl-decanoic acid;2-aminomethyl-5-cyclopropyl-4-methyl-pentanoic acid;2-aminomethyl-5-cyclobutyl-4-methyl-pentanoic acid;2-aminomethyl-5-cyclopentyl-4-methyl-pentanoic acid;2-aminomethyl-5-cyclohexyl-4-methyl-pentanoic acid;2-aminomethyl-6-cyclopropyl-4-methyl-hexanoic acid;2-aminomethyl-6-cyclobutyl-4-methyl-hexanoic acid;2-aminomethyl-6-cyclopentyl-4-methyl-hexanoic acid;2-aminomethyl-6-cyclohexyl-4-methyl-hexanoic acid;2-aminomethyl-7-cyclopropyl-4-methyl-heptanoic acid;2-aminomethyl-7-cyclobutyl-4-methyl-heptanoic acid;2-aminomethyl-7-cyclopentyl-4-methyl-heptanoic acid;2-aminomethyl-7-cyclohexyl-4-methyl-heptanoic acid;2-aminomethyl-8-cyclopropyl-4-methyl-octanoic acid;2-aminomethyl-8-cyclobutyl-4-methyl-octanoic acid;2-aminomethyl-8-cyclopentyl-4-methyl-octanoic acid;2-aminomethyl-8-cyclohexyl-4-methyl-octanoic acid; (2R,4S)-2-aminomethyl-5-cyclopropyl-4-methyl-pentanoic acid; (2R,4S)-2-aminomethyl-5-cyclobutyl-4-methyl-pentanoic acid; (2R,4S)-2-aminomethyl-5-cyclopentyl-4-methyl-pentanoic acid; (2R,4S)-2-aminomethyl-5-cyclohexyl-4-methyl-pentanoic acid; (2R,4S)-2-aminomethyl-6-cyclopropyl-4-methyl-hexanoic acid; (2R,4S)-2-aminomethyl-6-cyclobutyl-4-methyl-hexanoic acid; (2R,4S)-2-aminomethyl-6-cyclopentyl-4-methyl-hexanoic acid; (2R,4S)-2-aminomethyl-6-cyclohexyl-4-methyl-hexanoic acid; (2R,4S)-2-aminomethyl-7-cyclopropyl-4-methyl-heptanoic acid; (2R,4S)-2-aminomethyl-7-cyclobutyl-4-methyl-heptanoic acid; (2R,4S)-2-aminomethyl-7-cyclopentyl-4-methyl-heptanoic acid; (2R,4S)-2-aminomethyl-7-cyclohexyl-4-methyl-heptanoic acid; (2R,4S)-2-aminomethyl-8-cyclopropyl-4-methyl-octanoic acid; (2R,4S)-2-aminomethyl-8-cyclobutyl-4-methyl-octanoic acid; (2R,4S)-2-aminomethyl-8-cyclopentyl-4-methyl-octanoic acid; (2R,4S)-2-aminomethyl-8-cyclohexyl-4-methyl-octanoic acid; (2R,4R)-2-aminomethyl-5-cyclopropyl-4-methyl-pentanoic acid; (2R,4R)-2-aminomethyl-5-cyclobutyl-4-methyl-pentanoic acid; (2R,4R)-2-aminomethyl-5-cyclopentyl-4-methyl-pentanoic acid; (2R,4R)-2-aminomethyl-5-cyclohexyl-4-methyl-pentanoic acid; (2R,4R)-2-aminomethyl-6-cyclopropyl-4-methyl-hexanoic acid; (2R,4R)-2-aminomethyl-6-cyclobutyl-4-methyl-hexanoic acid; (2R,4R)-2-aminomethyl-6-cyclopentyl-4-methyl-hexanoic acid; (2R,4R)-2-aminomethyl-6-cyclohexyl-4-methyl-hexanoic acid; (2R,4R)-2-aminomethyl-7-cyclopropyl-4-methyl-heptanoic acid; (2R,4R)-2-aminomethyl-7-cyclobutyl-4-methyl-heptanoic acid; (2R,4R)-2-aminomethyl-7-cyclopentyl-4-methyl-heptanoic acid; (2R,4R)-2-aminomethyl-7-cyclohexyl-4-methyl-heptanoic acid; (2R,4R)-2-aminomethyl-8-cyclopropyl-4-methyl-octanoic acid; (2R,4R)-2-aminomethyl-8-cyclobutyl-4-methyl-octanoic acid; (2R,4R)-2-aminomethyl-8-cyclopentyl-4-methyl-octanoic acid; and (2R,4R)-2-aminomethyl-8-cyclohexyl-4-methyl-octanoic acid.
 16. Apharmaceutical composition comprising a therapeutically effective amountof a compound according to claim 3, or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable carrier.
 17. A method oftreating a disorder or condition in a mammal, including a human, themethod comprising administering to a mammal in need of such treatment atherapeutically effective amount of a compound according to claim 3, ora pharmaceutically acceptable salt thereof, wherein the disorder orcondition is selected from inflammatory pain, chronic pain, acute pain,neuropathic pain, sleep disorders, hot flashes, fibromyalgia, oranxiety.
 18. A method according to claim 17, wherein the disorder orcondition is neuropathic pain.
 19. A pharmaceutical compositioncomprising a therapeutically effective amount of a compound according toclaim 7, or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier.
 20. A method of treating a disorderor condition in a mammal, including a human, the method comprisingadministering to a mammal in need of such treatment a therapeuticallyeffective amount of a compound according to claim 7, or apharmaceutically acceptable salt thereof, wherein the disorder orcondition is selected from inflammatory pain, chronic pain, acute pain,neuropathic pain, sleep disorders, hot flashes, fibromyalgia, oranxiety.
 21. A method according to claim 20, wherein the disorder orcondition is neuropathic pain.
 22. A compound according to claim 8, or apharmaceutically acceptable salt thereof, the compound selected from:2-aminomethyl-5-ethyl-heptanoic acid;2-aminomethyl-5-ethyl-6-methyl-heptanoic acid;2-aminomethyl-7-cyclopropyl-5-ethyl-heptanoic acid;2-aminomethyl-7-cyclobutyl-5-ethyl-heptanoic acid;2-aminomethyl-7-cyclopentyl-5-ethyl-heptanoic acid;2-aminomethyl-7-cyclohexyl-5-ethyl-heptanoic acid;2-aminomethyl-5-ethyl-octanoic acid;2-aminomethyl-5-ethyl-7-methyl-octanoic acid;2-aminomethyl-5-ethyl-nonanoic acid;2-aminomethyl-5-ethyl-8-methyl-nonanoic acid;2-aminomethyl-6-cyclopropyl-5-methyl-hexanoic acid;2-aminomethyl-6-cyclobutyl-5-methyl-hexanoic acid;2-aminomethyl-6-cyclopentyl-5-methyl-hexanoic acid;2-aminomethyl-6-cyclohexyl-5-methyl-hexanoic acid;2-aminomethyl-7-cyclopropyl-5-methyl-heptanoic acid;2-aminomethyl-7-cyclobutyl-5-methyl-heptanoic acid;2-aminomethyl-7-cyclopentyl-5-methyl-heptanoic acid;2-aminomethyl-7-cyclohexyl-5-methyl-heptanoic acid;2-aminomethyl-8-cyclopropyl-5-methyl-octanoic acid;2-aminomethyl-8-cyclobutyl-5-methyl-octanoic acid;2-aminomethyl-8-cyclopentyl-5-methyl-octanoic acid;2-aminomethyl-8-cyclohexyl-5-methyl-octanoic acid;2-aminomethyl-5-methyl-heptanoic acid; 2-aminomethyl-5-methyl-octanoicacid; 2-aminomethyl-5-methyl-nonanoic acid;2-aminomethyl-8-methyl-nonanoic acid; (2R,6S)-2-aminomethyl-6-cyclopropyl-5-methyl-hexanoic acid; (2R,6S)-2-aminomethyl-6-cyclobutyl-5-methyl-hexanoic acid; (2R,6S)-2-aminomethyl-6-cyclopentyl-5-methyl-hexanoic acid; (2R,6S)-2-aminomethyl-6-cyclohexyl-5-methyl-hexanoic acid; (2R,6S)-2-aminomethyl-7-cyclopropyl-5-methyl-heptanoic acid; (2R,6S)-2-aminomethyl-7-cyclobutyl-5-methyl-heptanoic acid; (2R,6S)-2-aminomethyl-7-cyclopentyl-5-methyl-heptanoic acid; (2R,6S)-2-aminomethyl-7-cyclohexyl-5-methyl-heptanoic acid; (2R,6S)-2-aminomethyl-8-cyclopropyl-5-methyl-octanoic acid; (2R,6S)-2-aminomethyl-8-cyclobutyl-5-methyl-octanoic acid; (2R,6S)-2-aminomethyl-8-cyclopentyl-5-methyl-octanoic acid; (2R,6S)-2-aminomethyl-8-cyclohexyl-5-methyl-octanoic acid; (2R,6S)-2-aminomethyl-5-methyl-heptanoic acid; (2R,6S)-2-aminomethyl-5-methyl-octanoic acid; (2R,6S)-2-aminomethyl-5-methyl-nonanoic acid; (2R,6R)-2-aminomethyl-6-cyclopropyl-5-methyl-hexanoic acid; (2R,6R)-2-aminomethyl-6-cyclobutyl-5-methyl-hexanoic acid; (2R,6R)-2-aminomethyl-6-cyclopentyl-5-methyl-hexanoic acid; (2R,6R)-2-aminomethyl-6-cyclohexyl-5-methyl-hexanoic acid; (2R,6R)-2-aminomethyl-7-cyclopropyl-5-methyl-heptanoic acid; (2R,6R)-2-aminomethyl-7-cyclobutyl-5-methyl-heptanoic acid; (2R,6R)-2-aminomethyl-7-cyclopentyl-5-methyl-heptanoic acid; (2R,6R)-2-aminomethyl-7-cyclohexyl-5-methyl-heptanoic acid; (2R,6R)-2-aminomethyl-8-cyclopropyl-5-methyl-octanoic acid; (2R,6R)-2-aminomethyl-8-cyclobutyl-5-methyl-octanoic acid; (2R,6R)-2-aminomethyl-8-cyclopentyl-5-methyl-octanoic acid; (2R,6R)-2-aminomethyl-8-cyclohexyl-5-methyl-octanoic acid; (2R,6R)-2-aminomethyl-5-methyl-heptanoic acid; (2R,6R)-2-aminomethyl-5-methyl-octanoic acid; and (2R,6R)-2-aminomethyl-5-methyl-nonanoic acid.
 23. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundaccording to claim 8, or a pharmaceutically acceptable salt thereof, anda pharmaceutically acceptable carrier.
 24. A method of treating adisorder or condition in a mammal, including a human, the methodcomprising administering to a mammal in need of such treatment atherapeutically effective amount of a compound according to claim 8, ora pharmaceutically acceptable salt thereof, wherein the disorder orcondition is selected from inflammatory pain, chronic pain, acute pain,neuropathic pain, sleep disorders, hot flashes, fibromyalgia, oranxiety.
 25. A method according to claim 24, wherein the disorder orcondition is neuropathic pain.
 26. A compound selected from thefollowing and their pharmaceutically acceptable salts:2-aminomethyl-3-(1-methyl-cyclopropyl)-propionic acid;2-aminomethyl-3-(1-ethyl-cyclopropyl)-propionic acid;2-aminomethyl-3-(1-propyl-cyclopropyl)-propionic acid;2-aminomethyl-3-(1-isopropyl-cyclopropyl)-propionic acid;2-aminomethyl-3-(1-butyl-cyclopropyl)-propionic acid;2-aminomethyl-3-(1-isobutyl-cyclopropyl)-propionic acid;2-aminomethyl-3-[1-(4-methyl-pentyl)-cyclopropyl]-propionic acid;2-aminomethyl-3-(1-methyl-cyclobutyl)-propionic acid;2-aminomethyl-3-(1-ethyl-cyclobutyl)-propionic acid;2-aminomethyl-3-(1-propyl-cyclobutyl)-propionic acid;2-aminomethyl-3-(1-methyl-cyclopentyl)-propionic acid;2-aminomethyl-3-(1-ethyl-cyclopentyl)-propionic acid;2-aminomethyl-3-(1-propyl-cyclopentyl)-propionic acid;2-aminomethyl-3-(1-methyl-cyclohexyl)-propionic acid;2-aminomethyl-3-(1-ethyl-cyclohexyl)-propionic acid;2-aminomethyl-3-(1-propyl-cyclohexyl)-propionic acid;2-aminomethyl-4-cyclopropyl-butyric acid;2-aminomethyl-4-(1-methyl-cyclopropyl)-butyric acid;2-aminomethyl-4-(1-ethyl-cyclopropyl)-butyric acid;2-aminomethyl-4-cyclobutyl-butyric acid;2-aminomethyl-4-(1-methyl-cyclobutyl)-butyric acid;2-aminomethyl-4-(1-ethyl-cyclobutyl)-butyric acid;2-aminomethyl-4-cyclopentyl-butyric acid;2-aminomethyl-4-(1-methyl-cyclopentyl)-butyric acid;2-aminomethyl-4-(1-ethyl-cyclopentyl)-butyric acid;2-aminomethyl-4-cyclohexyl-butyric acid;2-aminomethyl-4-(1-methyl-cyclohexyl)-butyric acid; and2-aminomethyl-4-(1-ethyl-cyclohexyl)-butyric acid.
 27. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundaccording to claim 26, or a pharmaceutically acceptable salt thereof,and a pharmaceutically acceptable carrier.
 28. A method of treating adisorder or condition in a mammal, including a human, the methodcomprising administering to a mammal in need of such treatment atherapeutically effective amount of a compound according to claim 26, ora pharmaceutically acceptable salt thereof, wherein the disorder orcondition is selected from inflammatory pain, chronic pain, acute pain,neuropathic pain, sleep disorders, hot flashes, fibromyalgia, oranxiety.
 29. A method according to claim 28, wherein the disorder orcondition is neuropathic pain.